Benzoxepines

ABSTRACT

The subject of the invention is compounds of general formula: ##STR1## in which: X represents O or CHR, 
     R 1 , R 2 , R 3  and R 4 , which are identical or different, represent a hydrogen atom or a C 1  -C 7  alkyl group, it being possible for R 1  to additionally form a bond with R; 
     R 5  represents a hydrogen atom, a hydroxyl group or R 5 , taken together with R 7 , forms a bond or a &gt;O; group; 
     R 6  represents a group of formula: ##STR2##  in which R 10  and R 11 , taken together with the carbon atom to which they are attached, form a nitrogenous heterocyclic group, and their N-oxides and pharmaceutically acceptable salts. These compounds are powerful activators of potassium channels.

This application is a 371 of PCT/EP93/03445 now WO 94/13658.

The subject of the present invention is new heterocyclic compoundshaving a pharmacological activity in the activation of potassiumchannels.

Activators of potassium channels or potassium agonists have the propertyof activating the potassium channels of the cell membrane by openingthese channels or prolonging their opening. This results intransmembrane ionic movements and, inter alia, a decrease in freeintracellular Ca⁺⁺ ions which causes relaxation of smooth muscle fibres.

This therapeutic potentiality makes it possible today for great hopes tobe placed in potassium agonists. Among the most studied fields, arterialhypertension, angina and asthma are the most often mentioned. Largefamilies of activators of potassium channels are already recognized fortheir relaxant properties.

A family of benzopyran derivatives has formed the subject of manypublications in this field.

These compounds correspond to the following general formula A: ##STR3##

EP-0,076,075 describes compounds of general formula A, where ##STR4##represents a pyrrolidone. DE-3,726,261 describes compounds of generalformula A, where ##STR5## represents a pyridone.

Another benzopyran family corresponds to the formula B below; it isdescribed in EP-0,298,452: ##STR6##

W0-89/11477 and EP-0,360,131 relate to benzoxepines of general formulaC: ##STR7## where X represents a nitrogenous ring connected via thenitrogen atom to the 5-position of the benzoxepines, such as a2-oxo-1-pyrrolidinyl and 2-oxo-1-pyridyl group for the first and a2-oxo-1-pyridyl group or a 4-fluorobenzoylamino group for the second.

R₃, R₄, R₅ and R₆ represent a hydrogen atom or a lower alkyl group andR₁ and R₂ a hydrogen atom or a nitrile, arylsulfonyl or nitro group.

Novel compounds possessing a benzocycloheptene or benzoxepine ringsystem, which show notable effects on the activation of potassiumchannels, have now been discovered.

The subject of the invention is compounds of general formula: ##STR8##in which: X represents O, or CHR, R being a hydrogen atom or R, takentogether with R₁, forming a bond,

R₁, R₂, R₃ and R₄, which are identical or different, represent ahydrogen atom or a C₁ -C₇ alkyl group, it being possible for R₁ toadditionally form a bond with R;

R₅ represents a hydrogen atom, a hydroxyl group or R₅, taken togetherwith R₇, forms a bond or a >O; group;

R₆ represents a group of formula: ##STR9## in which R₁₀ and R₁₁, takentogether with the carbon atom to which they are attached, form anoptionally aromatic mono- or bicyclic nitrogenous heterocyclic grouphaving from 3 to 11 members, including 1 or 2 nitrogen atoms, optionallysubstituted on the carbon atoms by 1 to 7 groups chosen from hydroxyl,nitro, cyano, C₁ -C₇ alkyl or C₁ -C₇ alkoxy, it being possible for atleast one of the nitrogen atoms of the heterocycle to be N-oxidized;

R₇ represents a hydrogen atom or a hydroxyl, C₁ -C₇ alkoxy or C₁ -C₇acyloxy group or R₅ and R₇ together form a bond or a >O group;

R₈ and R₉, which are identical or different, represent a hydrogen orhalogen atom, a hydroxyl, nitro, cyano, trifluoromethyl,trifluoromethoxy, pentafluoroethyl, C₁ -C₇ alkyl, C₁ -C₇ alkoxy, C₁ -C₇alkylthio, C₁ -C₇ acylthio, C₁ -C₇ alkylsulfonyl or C₁ -C₇ alkylsulfinylgroup, a group of formulae: ##STR10## in which R₁₂ and R₁₃, which areidentical or different, represent a hydrogen atom or a C₁ -C₇ alkylgroup, or R₈ and R₉ represent a C₆ -C₁₀ aryl, (C₆ -C₁₀)arylsulfonyl or(C₆ -C₁₀)arylsulfinyl group, optionally substituted by one to sixsubstituents chosen from halo, hydroxyl, nitro, cyano, carboxyl,carbamoyl, trifluoromethyl, trifluoromethoxy, pentafluoroethyl, C₁ -C₇alkyl, C₁ -C₇ alkoxy, C₁ -C₇ alkylthio, C₁ -C₇ acylthio, C₁ -C₇alkylsulfonyl or C₁ -C₇ alkylsulfinyl,

or R₈ and R₉, which are identical or different, represent a heterocyclehaving from 3 to 11 members in the ring including 1 to 4 hetereoatoms,which are identical or different, chosen from O, S and N, optionallysubstituted by one to six substituents chosen from halo, hydroxyl,nitro, cyano, carboxyl, carbamoyl, trifluoromethyl, trifluoromethoxy,pentafluoroethyl, C₁ -C₇ alkyl, C₁ -C₇ alkoxy, C₁ -C₇ alkylthio, C₁ -C₇acylthio, C₁ -C₇ alkylsulfonyl or C₁ -C₇ alkylsulfinyl,

or R₈ and R₉ together form a group (CH₂)_(n), n being a number from 1 to6, or R₈ and R₉ together form a heterocycle having from 3 to 11 membersincluding 1 to 4 heteroatoms, which are identical or different, chosenfrom O, S and N, optionally substituted by one to six substituentschosen from halo, hydroxyl, nitro, cyano, carboxyl, carbamoyl,trifluoromethyl, trifluoromethoxy, pentafluoroethyl, C₁ -C₇ alkyl, C₁-C₇ alkoxy, C₁ -C₇ alkylthio, C₁ -C₇ acylthio, C₁ -C₇ alkylsulfonyl orC₁ -C₇ alkylsulfinyl,

and their N-oxides and their pharmaceutically acceptable salts.

"C₁ -C₇ alkyl group" means the groups containing a linear or branched C₁-C₇ chain, especially the methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, isobutyl, pentyl, hexyl and heptyl groups.

"C₁ -C₇ alkoxy group" means the groups containing a linear or branchedC₁ -C₇ chain, especially the methoxy, ethoxy, propoxy, butoxy, pentoxy,hexyloxy and heptyloxy groups.

"C₁ -C₇ acyloxy group" means the alkyl groups containing a linear orbranched C₁ -C₇ chain linked to a carbonyloxy functional group,especially the acetoxy and propionyloxy groups.

"C₁ -C₇ alkylthio group" means the alkyl groups containing a linear orbranched C₁ -C₇ chain linked to a sulfur atom, especially themethylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio andheptylthio groups.

"C₁ -C₇ alkylsulfonyl group" means the alkyl groups containing a linearor branched C₁ -C₇ chain linked to a --SO₂ -- sulfonyl group, especiallythe methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl,pentylsulfonyl, hexylsulfonyl and heptylsulfonyl groups.

"C₁ -C₇ alkylsulfinyl group" means the alkyl groups containing a linearor branched C₁ -C₇ chain linked to a --SO-- sulfinyl group, especiallythe methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl,pentylsulfinyl, hexylsulfinyl and heptylsulfinyl groups.

"C₆ -C₁₀ aryl group" means the mono- or bicyclic carbocyclic aromaticgroups, especially the phenyl, naphthyl or indenyl groups.

The term "halogen" means the fluorine, chlorine, bromine or iodineatoms.

The heterocycle containing from 3 to 11 atoms, including 1 to 4hetereoatoms chosen from O, S and N, can be aromatic or nonaromatic,monocyclic or bicyclic, and is in particular a pyridyl, imidazolyl,furyl, tetrahydrofuryl, furazanyl, thienyl, aziridinyl, oxiranyl,azetidinyl, quinolyl, tetrahydroquinolyl and tetrazolyl group.

When R₈ and R₉ together form a heterocycle having from 3 to 11 members,including 1 to 4 identical or different hetereoatoms chosen from O, Sand N, they represent, especially with the phenyl group to which theyare attached, a quinolyl, isoquinolyl, benzimidazolyl, benzofuryl,benzothienyl and benzoxadiazolyl group.

The R₆ group is in particular a 2-pyridyl, 2-pyridyl N-oxide, 3-pyridyl,3-pyridyl N-oxide, 4-pyridyl, 3-hydroxy-4-pyridyl, 2-pyrimidyl,2-pyrimidyl N-oxide, 6-pyrimidyl, 6-pyrimidyl N-oxide, 2-quinolyl,2-quinolyl N-oxide, 1-isoquinolyl and 1-isoquinolyl N-oxide group,optionally substituted on the carbon atoms by 1 to 3 substituents chosenfrom hydroxyl, nitro, cyano, C₁ -C₇ alkyl and C₁ -C₇ alkoxy.

The physiologically acceptable salts of the compounds of formula Icomprise the salts formed with metals such as sodium, potassium, calciumand magnesium or salts of organic acids such as oxalic, fumaric, maleic,citric, methanesulfonic and lactic acids.

The N-oxides of formula I are the compounds in which 1 or more of thenitrogen atoms of the R₆ group are oxidized.

The term "trans" used for the compounds which carry asymmetric carbonatoms in the rings shows that two substituents are found on either sideof a central plane of the ring, and the term "cis" is applied for twosubstituents which are found on the same side of the same central planeof the ring.

The preferred compounds of general formula I are those in which Xrepresents an oxygen atom.

Advantageously, R₁ and R₂ represent a hydrogen atom and/or R₅ representsa hydrogen atom.

Advantageously, R₇ is chosen from a hydrogen atom or the hydroxyl,methoxy and acetoxy group.

A first preferred family of compounds of the present inventioncorrespond to the compounds of general formula II: ##STR11## in which Xrepresents O or CH--R, and R, R₅, R₆, R₇, R₈ and R₉ are as definedabove.

Carbon atoms 4 and 5 of the formula II can together or independentlyrepresent a chiral centre. Derivatives such as optical isomers,racemates, cis or trans derivatives, enantiomers and diastereoisomersform part of the invention.

Among the preferred compounds of formula II, it is possible inparticular to mention the following compounds:

3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol;

7-fluoro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol;

7-bromo-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol;

8-bromo-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol;

7-bromo-3,3-dimethyl-5-(3-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol;

5-acetyloxy-7-bromo-3,3-dimethyl -5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepine;

7-bromo-4,5-epoxy-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepine;

7-bromo-5-methoxy-3,3-dimethyl-5-(2-pyridylN-oxide)-3,4,5-tetrahydro-1-benzoxepine;

7-ethyl-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol;

7-methoxy-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol;

3,3-dimethyl-7-(1-methylpropyl)-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol;

3,3-dimethyl-5-(2-pyridylN-oxide)-7-trifluoromethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-ol;

3,3-dimethyl-5-(2-pyridyl N-oxide)-7-trifluoromethoxy-2,3,4,5-tetrahydro-1-benzoxepin-5-ol;

3,3-dimethyl-7-phenyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol;

8-chloro-7-fluoro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol;

3,3-dimethyl-5-(3-pyridylN-oxide)-7-trifluoromethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-ol;

6,8-dichloro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol;

7,8-dichloro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol;

7,8-dichloro-3,3-dimethyl-5-(3-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol;

7,8-dimethoxy-3,3-dimethyl -5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol;

7,9-dichloro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol.

A second preferred family of compounds of the present inventioncorrespond to the compounds of general formula III: ##STR12## in which Xrepresents O or CH--R, and R, R₆, R₈ and R₉ are as defined above.

Among the preferred compounds of formula III, it is possible inparticular to mention the following compounds:

3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;

7-fluoro-3,3-dimethyl -5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;

7-bromo-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;

7-chloro-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;

8-bromo-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;

7-bromo-3,3-dimethyl-5-(3-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;

3,3,7-trimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;

7-ethyl-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;

3,3-dimethyl-7-(1-methylpropyl)-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine;

7-isopropyl-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine;

7-methoxy-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;

3,3-dimethyl-5-(2-pyridylN-oxide)-7-trifluoromethyl-3-dihydro-1-benzoxepine;

2,3-dimethyl-5-(2-pyridylN-oxide)-8-trifluoromethyl-3-dihydro-1-benzoxepine;

3,3-dimethyl-5-(2-pyridylN-oxide)-7-trifluoromethoxy-3-dihydro-1-benzoxepine;

3,3-dimethyl-7-methylsulfinyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine;

3,3-dimethyl-7-methylsulfonyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine;

3,3-dimethyl-7-methylsulfonyl-5-(2-pyridylN-oxide)-3-dihydro-1-benzoxepine;

7-cyano-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;

8-cyano-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;

3,3-dimethyl-5-(2-pyridylN-oxide)-7-pentafluoroethyl-3-dihydro-1-benzoxepine;

3,3-dimethyl-7-phenyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;

3,3-dimethyl-7-nitro-5-(4-nitro-2-pyridylN-oxide)-3-dihydro-1-benzoxepine;

7,8-dichloro-3,3-dimethyl-5-(3-pyridyl N-oxide)-3-dihydro-1-benzoxepine;

6,8-dichloro-3,3-dimethyl-5-(2-pyridyl N-oxide)-3-dihydro-1-benzoxepine;

7,9-dichloro-3,3-dimethyl-5-(2-pyridyl N-oxide)-3-dihydro-1-benzoxepine;

8,9-dichloro-3,3-dimethyl-5-(2-pyridyl N-oxide)-3-dihydro-1-benzoxepine;

7,8-dichloro-3,3-dimethyl-5-(2-pyridyl N-oxide)-3-dihydro-1-benzoxepine;

7,8-difluoro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine;

9-ethyl-7-fluoro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine;

8-cyano-3,3,7-trimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;

7-cyano-3,3,8-trimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;

7,8-dimethoxy-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine;

8-chloro-7-fluoro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine;

3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,7,8,9,10-hexa-hydro-1-naphth[2,3-b]oxepine;

8-cyano-3,3-dimethyl-1-(2-pyridylN-oxide)-4,5-dihydro-3H-benzo[4,3-f]cycloheptene;

3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine-7-carboxamide;

3,3-dimethyl-7-phenylsulfonyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine;

7-chloro-8-ethyl-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine;

8-bromo-3,3-dimethyl-1-(2-pyridylN-oxide)-3H-benzo[f]-cyclohepta-1,4-diene.

The compounds of the invention can be prepared by a process comprising:

a) the reaction of a ketone of general formula IV: ##STR13## in which X,R₁, R₂, R₃ and R₄ are as defined above, and R₅ ', R₈ ' and R₉ 'respectively represent the optionally protected R₅, R₈ and R₉ groups asdefined above, with an organometallic compound of general formula:

    R.sub.6 '-R.sub.M                                          V

in which R₆ ' represents a group of formula: ##STR14## in which R₁₀ andR₁₁, taken together with the carbon atom to which they are attached,form an optionally aromatic, mono- or bicyclic nitrogenous heterocyclicgroup having from 3 to 11 members, including 1 or 2 nitrogen atoms, andoptionally substituted on the carbon atoms by 1 to 7 groups, optionallyprotected if necessary, chosen from hydroxyl, nitro, cyano, C₁ -C₇ alkylor C₁ -C₇ alkoxy; and

b) the deprotection of protected groups to produce a compound of generalformula VI: ##STR15## in which X, R₁, R₂, R₃, R₄, R₅, R₆, R₈ and R₉ areas defined above; and optionally either

c1) the reaction of the compound of general formula VI thus obtainedwith a reactant of general formula VII:

    R.sub.14 -Y                                                VII

in which R₁₄ represents a C₁ -C₇ alkyl or C₁ -C₇ acyl group and Yrepresents a leaving group, to produce a compound of general formula Iin which R₇ represents a C₁ -C₇ alkoxy or C₁ -C₇ acyloxy group,respectively; or

c2) the dehydration of the compound of general formula VI obtained in b)in the presence of an acid or of an acid chloride to produce a compoundof following general formula I: ##STR16## in which X, R₁, R₂, R₃, R₄,R₅, R₆, R₈ and R₉ are as defined above; and optionally

d) the reaction of the compound of formula I obtained in Stage c2) witha peroxide to produce a compound of general formula I in which R₅ and R₇together form a O group; and optionally

e) the reaction of the compound of general formula VI obtained in Stageb) or of the compound of general formula I obtained in Stage c1), c2) ord) with an oxidizing agent to form a corresponding N-oxide compound;and/or optionally

f) the reaction of the compound of general formula VI obtained in Stageb) or of the compound of general formula I obtained in Stage c1), c2) ord) with a pharmaceutically acceptable inorganic or organic acid to forma corresponding salt.

In the reaction of Stage a), a compound of formula IV as defined aboveis advantageously reacted with an organolithium compound of formulaLiR'₆, R'₆ being as defined above.

The compounds of formula LiR'₆ can be prepared in a known way by aperson skilled in the art, for example by reacting a compound of theformula R'₆ Br, R'₆ being as defined above, with n-butyllithium in anorganic solvent such as diethyl ether or tetrahydrofuran, optionally inthe presence of hexamethylphosphoramide or of 1,3-dimethylimidazolidoneat a temperature between -110° C. and the reflux temperature of thesolvent, or of the mixture of solvents, for a time between 4 hours and24 hours.

When the compounds of formula IV or V comprise OH groups, the latter areprotected by a protective group of the hydroxyl functional group knownto a person skilled in the art, for example an SiMe₃ or SiMe₃ tBu group.

The reaction of Stage a) takes place in an inert organic solvent, inparticular diethyl ether, THF or hexane, at a temperature between -78°C. and -20° C., followed by the addition of a dilute acid to release thealcohol from the lithium alkoxide complex formed.

The deprotection reaction of Stage b) is carried out by an acidtreatment in aqueous medium or by the use of fluoride (for example oftetrabutylammonium fluoride) in tetrahydrofuran at a temperature between-20° C. and 100° C., preferably 25° C.

In Stage c1), the leaving group Y is in particular a halogen atom or analkyl- or arylsulfonyloxy group, in particular a mesyloxy or tosyloxygroup.

Preferably, an acyl halide or an alkyl halide is used in the presence ofa Lewis base in a solvent such as dimethylformamide.

The reaction for the removal of H₂ O in Stage c2) is advantageouslycarried out in acid medium and in the presence of an organic solvent,such as benzene, toluene or xylene, the acid being in particularpara-toluenesulfonic acid or sulfuric acid.

The acid can also consist of an acid chloride such as the chloride ofmethanesulfonic acid, in the presence of a solvent such as chloroform,dichloromethane or dichloroethane.

The reaction is advantageously carried out at the reflux temperature ofthe solvent.

The reaction of Stage d) takes place in the presence of a peroxide, inparticular a peracid, such as peracetic acid, perbenzoic acid,perphthalic acid or 3-chloroperbenzoic acid. The amount of peroxide usedcan vary from 1 to 4 equivalents depending on the compound to beoxidized. The solvent used is preferably water, acetic acid orchlorinated solvents such as dichloromethane, chloroform ordichloroethane. The temperature of the reaction is advantageouslybetween -20° C. and the reflux temperature of the solvent.

The reaction of Stage e) takes place in the presence of an oxidizingagent, in particular a peracid such as mentioned above (for example3-chloroperbenzoic acid) in a solvent such as dichloromethane.

The ketones prepared are in particular:

7-bromo-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(53.2 Pa=0.4 mm Hg) =117°-121° C.

7-chloro-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(66.5 Pa=0.5 mm Hg) =80°-100° C.

7-cyano-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-one M.p.=114° C.

7-ethyl-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(39.9 Pa=0.3 mm Hg) =97°-104° C.

7-fluoro-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(53.2 Pa=0.4 mm Hg) =102°-108° C.

7-isopropyl-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(53.2 Pa=0.4 mm Hg) =112°-122° C.

7-methoxy-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(33.25 Pa=0.25 mm Hg) =122°-126 C.

3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-one B.P..sub.(103.4Pa=0.8 mm Hg) =90° C.

3,3,7-trimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-one B.P..sub.(53.2Pa=0.4 mm Hg) =90°-104° C.

7-(1-methylpropyl)-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(53.2 Pa=0.4 mm Hg) =115°-120° C.

7-methylthio-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(79.8 Pa=0.6 mm Hg) =125°-135° C.

7-pentafluoroethyl-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-one

7-phenyl-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(26.6 Pa=0.2 mm Hg) =135°-140° C.

7-phenylthio-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-one

7-trifluoromethoxy-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(2128 Pa=16 mm Hg) =135°-138° C.

7-trifluoromethyl-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(133. Pa=1 mm Hg) =80°-100° C.

8-bromo-3,3-dimethyl-2,3,4,5-tetrahydro-1H-benzo[f]cyclohepten-1-oneM.p.=94° C.

8-bromo-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(39.9 Pa=0.3 mm Hg) =108°-112° C.

8-trifluoromethyl-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(39.9 Pa=0.3 mm Hg) =85°-110° C.

9-bromo-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-one M.p.=86° C.

7-(2-methylpropyl)-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(53.2 Pa=0.4 mm Hg) =128°-138° C.

7-(2-methylpropyl)-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p.=128°-136° C.

7-bromo-8-methyl-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(53.2 Pa=0.4 mm Hg) =120°-130° C.

6,8-dichloro-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(106.4 Pa=0.8 mm Hg) =120° C.

7,8-dichloro-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-one M.p.=94°C.

7,9-dichloro-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(79.8 Pa=0.6 mm Hg) =120°-130° C.

8,9-dichloro-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-one

7-chloro-8-ethyl-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(53.2 Pa=0.4 mm Hg) =108°-112° C.

7-chloro-3,3,8-trimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(53.2 Pa=0.4 mm Hg) =115°-122° C.

7,8-difluoro-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-one M.p.=84°C.

7-fluoro-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-one B.p.M.p.=82° C.

7-fluoro-9-ethyl-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(79.8 Pa=0.6 mm Hg) =102°-106° C.

7,8-dimethoxy-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneM.p.=110° C.

7-methyl-8-bromo-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p..sub.(66.5 Pa=0.5 mm Hg) =125°-130° C.

7,8-dichloro-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-one M.p.=95°C.

3,3-dimethyl-2,3,4,5,7,8,9,10-octahydro-1-naphth[2,3-b]oxepin-5-oneB.p..sub.(53.2 Pa=0.4 mm Hg) =135°-150° C.

7(2-methylpropyl)-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneB.p.=128°-136° C.;

8-chloro-3,3-dimethyl-7-trifluoromethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneM.p.=80° C.;

7-bromo-8-chloro-3,3-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-oneM.p.=94° C.;

3,3-dimethyl-8-phenylthio-2,3,4,5-tetrahydro-1H-benzo[f]cycloheptane-1-one;

7,8-dichloro-3,3-dimethyl-2,3,4,5-tetrahydro-1H-benzo[f]cycloheptane-1-oneM.p.=74°

8-bromo-4,4-dimethyl-2,3,4,5-tetrahydro-1H-benzo[f]cycloheptane-1-one;

8-bromo-3,3-dimethyl-2,3,4,5-tetrahydro-1H-benzo[f]cycloheptane-1-oneM.p.=94° C.

The ketones of formula IV can be obtained by cyclization of the acids offormula VIII: ##STR17## in which x, R₁, R₂, R₃, R₄, R₅, R₈ and R₉ are asdefined above, according to the method described by Guy Fontaine(Annalen der Chemie, 1968, Volume 3, No. 3, page 180) for thepreparation of benzoxepines by cyclization of phenoxybutyric acids inthe presence of phosphoric acid, alone or as a mixture with an organicsolvent such as xylene, toluene or benzene, or by a Friedel-Craftsreaction from aluminium chloride and the chlorides of the corresponding4-phenoxybutanoic, 4-phenylthiobutanoic or 5-phenylpentanoic acids in asolvent such as CS₂ or nitrobenzene.

Other synthetic routes can also be used, in particular the Dieckmanncondensation reactions.

The acids of general formula VIII can be prepared when X represents O byreaction of a compound of general formula IX: ##STR18## in which R₈ andR₉ are as defined above, with a compound of general formula X: ##STR19##in which R₁, R₂, R₃, R₄ and R₅ are as defined above, according to themethod of Reppe W. (Annalen der Chemie, 1955, book 596, p. 158-224).

The reaction takes place by heating in butanol in the presence of NaOH.

The acids of general formula VIII can also be prepared by reacting aphenol of formula IX as defined above with a compound of general formulaXI: ##STR20## in which R₁, R₂, R₃, R₄ and R₅ are as defined above, Arepresents a halogen atom and B a lower alkyl or phenyl group, in asolvent such as DMF and in the presence of K₂ CO₃ or in acetone in thepresence of K₂ CO₃ and KI.

When X represents CHR, the acids of general formula VIII can be preparedaccording to Matbur K. C. and Singh V. P. (Proc. Natl. Acad. Sci. India.Sect A, 1981, 51 (2), p. 177 and 180), or according to Klaus Michael andMohr Peter (EP-0,315,071) by:

a) reaction of a compound of formula XII: ##STR21## with a compound offormula XIII or XIV: ##STR22## in which R₁, R₂, R₃, R₄ and R₅ are asdefined above, A represents a halogen atom and B a lower alkyl or phenylgroup, in the presence of AlCl₃ in a solvent like CS₂ or nitrobenzene,or in the absence of solvent, to produce a compound of general formulaXV: ##STR23## in which R₁, R₂, R₃, R₄, R₅, R₈, R₉ and B are as definedabove;

b) hydrolysis of the compound of general formula XV thus obtained

either in basic medium such as NaOH, KOH, NaHCO₃, for example inwater/alcohol medium,

or in acid medium:

to produce a compound of general formula XVI: ##STR24## in which R₁, R₂,R₃, R₄, R₅, R₈, and R₉ are as defined above, and

c) reduction of the carbonyl functional group of the compound of formulaXVI according to the WolffKishner reaction in the presence of an excessof hydrazine and of strong base, for example potassium hydroxide, indiethylene glycol or polyethylene glycol at high temperature.

The acids of formula VIII prepared are in particular:

4-phenoxy-3,3-dimethylbutanoic acid, B.p..sub.(13.3 Pa=0.1 mm Hg) =130°C.;

4-(4-bromophenoxy)-3,3-dimethylbutanoic acid, B.p..sub.(53.2 Pa=0.4 mmHg) =154°-162° C.;

4-(4-chlorophenoxy)-3,3-dimethylbutanoic acid, B.p..sub.(53.2 Pa=0.4 mmHg) =130°-145° C.;

4-(4-fluorophenoxy)-3,3-dimethylbutanoic acid, B.p..sub.(53.2 Pa=0.4 mmHg) =128°-134° C.;

4-(4-methylphenoxy)-3,3-dimethylbutanoic acid, B.p..sub.(53.2 Pa=0.4 mmHg) =130°-136° C.;

4-(4-ethylphenoxy)-3,3-dimethylbutanoic acid, B.p..sub.(53.2 Pa=0.4 mmHg) =132°-136° C.;

4-(4-isopropylphenoxy)-3,3-dimethylbutanoic acid, B.p..sub.(53.2 Pa=0.4mm Hg) =130°-142° C.;

4-[4-(1-methylpropyl)phenoxy]-3,3-dimethylbutanoic acid, B.p..sub.(53.2Pa=0.4 mm Hg) =155°-165° C.;

4-(4-methoxyphenoxy)-3,3-dimethylbutanoic acid, M.p.=69° C.;

4-(4-trifluoromethoxyphenoxy)-3,3-dimethylbutanoic acid, B.p..sub.(53.2Pa=0.4 mm Hg) =100°-120° C.;

4-(4-methylthiophenoxy)-3,3-dimethylbutanoic acid, B.p..sub.(106.4Pa=0.8 mm Hg) =150°-170° C.;

4-(4-phenylphenoxy)-3,3-dimethylbutanoic acid, M.p.=124° C.;

4-(3-bromophenoxy)-3,3-dimethylbutanoic acid, B.p..sub.(106.4 Pa=0.8 mmHg) =140°-160° C.;

4-(3,5-dichlorophenoxy)-3,3-dimethylbutanoic acid, B.p..sub.(53.2 Pa=0.4mm Hg) =130°-150° C.;

4-(3,4-dichlorophenoxy)-3,3-dimethylbutanoic acid, M.p.=66° C.;

4-(2,4-dichlorophenoxy)-3,3-dimethylbutanoic acid, B.p..sub.(66.5 Pa=0.5mm Hg) =150°-160° C.;

4-(2,3-dichlorophenoxy)-3,3-dimethylbutanoic acid, B.p..sub.(66.5 Pa=0.5mm Hg) =130°-160° C.;

4-(3,4-difluorophenoxy)-3,3-dimethylbutanoic acid, B.p..sub.(53.2 Pa=0.4mm Hg) 110°-134° C.;

4-(3-chloro-4-fluorophenoxy)-3,3-dimethylbutanoic acid, B.P..sub.(53.2Pa=0.4 mm Hg) =130°-145° C.;

4-(2-ethyl-4-fluorophenoxy)-3,3-dimethylbutanoic acid, B.P..sub.(53.2Pa=0.4 mm Hg) =123°-136° C.;

4-(3,4-dimethoxyphenoxy)-3,3-dimethylbutanoic acid, B.p..sub.(53.2Pa=0.4 mm Hg) =150°-170° C.;

4-(4-bromo-3-methylphenoxy)-3,3-dimethylbutanoic acid, B.p..sub.(53.2Pa=0.4 mm Hg) =130°-135° C.;

4-(3-bromo-4-methylphenoxy)-3,3-dimethylbutanoic acid, B.p..sub.(53.2Pa=0.4 mm Hg) =155°-160° C.;

4-(5,6,7,8-tetrahydro-2-naphthyloxy)-3,3-dimethylbutanoic acid, M.p.=85°C.;

4-[4-(2-methylpropyl)phenoxy]-3,3-dimethylbutanoic acid, B.p..sub.(665Pa=5 mm Hg) =160°-180° C.;

4-(4-chloro-3-ethylphenoxy)-3,3-dimethylbutanoic acid, B.p..sub.(53,2Pa=0,4 mm Hg) =160°-166° C.;

4-(4-chloro-3-methylphenoxy)-3,3-dimethylbutanoic acid, B.p..sub.(53,2Pa=0,4 mm Hg) =150°-158° C.;

4-(4-bromo-3-chlorophenoxy)-3,3-dimethyl-butanoic acid, B.p..sub.(53,2Pa=0,4 mm Hg) =150°-170° C.;

5-(4-bromophenyl)-3,3-dimethylpentanoic acid, M.p.=72° C.;

5-(3,4-dichlorophenyl)-3,3-dimethylpentanoic acid;

5-(4-bromophenyl)-4,4-dimethylpentanoic acid, M.p.=106°-108° C.

The compounds of the invention have excellent properties in theactivation of potassium channels and have a powerful relaxant effect onsmooth musculature. Consequently, they can be used as bronchodilators indisorders of the respiratory system, and in particular against asthmaand obstruction of the upper airways. They also have an advantage in thecontrol of hypertension and in the case of disorders of the contractionof the smooth musculature of the gastrointestinal tract, of the uterus,of the urinary tract, and in incontinence phenomena. They are useful inthe case of cardiovascular disorders other than hypertension, inparticular cardiac insufficiency, angina pectoris, cerebral andperipheral vascular pathologies and pulmonary hypertension. Thesecompounds are additionally active in the treatment of alopecia.

The "potassium channel activating" activity was measured by the rate ofexit of rubidium-86 from tracheal smooth muscle cell according to themethod described by Allen, S. L., Br. J. Pharmac., 1986, 87, p. 117-127and 89, p. 395-405.

Rate of the efflux of rubidium-86 in in vitro quinea pig trachea:

Male guinea pigs weighing 250 to 600 g are stunned and exsanguinated bysectioning the jugular. The trachea is rapidly freed and cleaned insitu. The parts removed are placed on hold in an oxygenated modifiedKrebs-Henseleit (M.K.H.) solution. When all the tracheae are removedeach is enriched in smooth muscle. The trachea is placed in acrystallizing dish containing the M.K.H. and a stream of O₂ /CO₂ at 37°C. Two longitudinal incisions are carefully made on both sides of themuscle strip at 1 mm from the latter. The tracheae are then equilibratedin a beaker containing 30 ml of M.K.H. for 30 minutes, after which therubidium-86 radioactive charge is added. A constant and sustainedgaseous flow rate is maintained throughout the manipulation.

The beaker is then replaced by another containing 25 ml of oxygenatedM.K.H. and 125 microcuries of ⁸⁶ Rb for 3 hours. The tracheae are washedtwice in succession in a beaker containing approximately 100 ml ofM.K.H. for 3 minutes.

The tracheae are introduced individually into a series of 10 mldisposable tubes. The latter are filled, 30 seconds before immersion ofthe tracheae, with 4 ml of oxygenated M.K.H. There are then carried outan immersion of the tracheae for 5 minutes and 5 rinsings of 10 minutesand then efflux periods of 3 minutes. A first group of tubes are usedfor estimating the base efflux: they contain 10 μl of pure DMSO plus 4ml of M.K.H. A second group of tubes makes it possible to bring thesample into contact with a concentration of product to be tested lastingseven periods of 3 minutes. The products are used in the form of mothersolutions containing 40.1 mmol of pure DMSO, then diluted in the samesolvent and introduced in the set amount of 10 μl per 4 ml of M.K.H. Thecounting is carried out by the Cerenkov effect.

The effective concentration of the product which increases the baseefflux rate by 25% (EC_(25%)) is determined.

The efflux rate of the tracer is expressed as percentage of release perminute with respect to the total amount of tracer at the time underconsideration.

The EC_(25%) is calculated by linear regression from the relationship:Maximum efflux in the presence of product with respect to the baseefflux as a function of the logarithm of the concentration.

The results obtained with representative compounds of the invention arereported in Table I below.

                  TABLE I                                                         ______________________________________                                        Results of the activating activity of the compounds of                        the invention for potassium channels                                                        Efflux of .sup.86 Rb                                            Compound      EC.sub.25% (μmol)                                            ______________________________________                                         91           1.1                                                             100           2.0                                                             104           0.7                                                             109           1.8                                                             111           0.8                                                             ______________________________________                                    

The bronchodilating activity was measured in vivo by the method ofKonzett H. and Rossler R. (Arch. Exp. Pathol. Pharmak., 1940, 195, p. 71to 74) and Duhault J. et al. (Arzneim. Forsch./Drug. res., 1987, 37, p.1353 to 1362).

Measurement of the bronchodilating activity:

Dukin-Hartley guinea pigs (400-500 g) are prepared according to themethodology described by Konzett and Rossler. The animals areanaesthetized by an intraperitoneal injection of urethane (1.5 g/kg) anda tracheotomy is prepared for artificial respiration (45 cycles/min;respiratory volume 10 ml/kg).

The animal is connected to a respiratory pump, which is adjusted todeliver a volume of 1 ml per 100 g of body weight of the guinea pig. Itis connected to a recorder via a pressure sensor.

A catheter is placed in the jugular for the I.V. injections.

An I.V. injection of gallamine and propanolol is carried out. Afterstabilizing the pulmonary pressure for 30 minutes, an I.V. injection ofhistamine is carried out every 10 minutes until reproducibility isachieved; at that point, the test product is injected 10 minutes afterthe last spasm. Histamine is tested 5 minutes and 15 minutes after theinjection of the product and the effective dose for a 50% inhibition iscalculated.

The results obtained with representative compounds of the invention arereported in Table II below.

                  TABLE II                                                        ______________________________________                                        Results of the bronchodilating activity of the compounds                      of the invention                                                                            Bronchospasm ED.sub.50 mg/kg                                    Compound        at 5 min at 15 min                                            ______________________________________                                         91             0.100    --                                                   100             0.069    0.101                                                104             0.038    0.210                                                109             0.086    0.331                                                111             0.049    0.100                                                114             0.040    0.300                                                118             0.150    0.200                                                119             0.310    0.530                                                ______________________________________                                    

The compounds of the invention are active in man and animals, inparticular in mammals, in particular in dogs, guinea pigs, rabbits, ratsand mice.

The compounds of the invention are non-toxic.

Another subject of the invention is a pharmaceutical compositioncomprising, as active ingredient, a compound according to the inventionas defined above, in combination with a pharmaceutically acceptablevehicle.

These pharmaceutical compositions are used in oral, intravenous,intraarterial, cutaneous or intestinal administration or as an aerosol.Moreover, these new products have a long-lasting action, whatever themode of administration.

The products of the general formula I will be combined in thepharmaceutical form with excipients, flavours and dyes, which aresuitable for forming, for example, tablets, which can additionally beprovided in the liposomal, microcapsule or nanocapsule form, or in theform of coated tablets, gelatin capsules, solutions, injectablesolutions, suppositories, aerosols or creams. The excipients used canbe, for example, microcrystalline cellulose, lactose, polyvidone, starchsodium glycolate, talc or magnesium stearate. The excipients for theliposomal or microcapsule forms can be poly(alkyl cyanoacrylates) orphospholipids.

The coating of the tablets can be carried out with additives such ashydroxypropyl methylcellulose, various acrylic polymers, propyleneglycol and titanium dioxide.

The preparations for oral administration can contain artificial flavoursand sweeteners such as sugar or aspartame.

The injectable solution preparations will be made up with water whichwill contain stabilization agents, solubilization agents, such as sodiumchloride, mannitol and sorbitol, and/or buffers necessary for theinjectable solutions.

The preparations for suppositories can use excipients such assemi-synthetic glycerides.

The preparations for creams will be made, inter alia, by the addition ofnonionic surface-active agents.

The preparations for aerosol administration can be made from themicronized active principle, in combination with a surface-active agentsuch as sorbitan trioleate, in a carrier gas such as CFC-11 and -12 orany other substituted carrier gas.

The compounds of the invention can also be used in combination with anyother substance of therapeutic use, for example diuretics,beta-blockers, PAF-acether antagonists, TxA₂ antagonists, convertingenzyme inhibitors, beta-adrenergic inhibitors and anti-arrhythmics.

The daily doses of active principle, administered once or a number oftimes, can be between 0.0001 and 100 mg/kg of body weight and preferablybetween 0.001 and 1 mg/kg. However, these limits can be exceeded in theevent of necessity.

A formulation example of a tablet and of a gelatin capsule according tothe invention will be given below.

    ______________________________________                                        Tablet formulation example:                                                   Compound of formula 91                                                                             5 mg                                                     Microcrystalline cellulose                                                                         90 mg                                                    Lactose             144 mg                                                    Starch sodium glycolate                                                                            10 mg                                                    Magnesium stearate   1 mg                                                                         250 mg                                                    Gelatin capsule formulation example:                                          Compound of formula 111                                                                            10 mg                                                    Microcrystalline cellulose                                                                        109 mg                                                    Lactose             100 mg                                                    Starch               30 mg                                                    Magnesium stearate   1 mg                                                                         250 mg                                                    ______________________________________                                    

The following examples illustrate the invention in a non-limiting way.

In the proton nuclear magnetic resonance (¹ H NMR) data, the followingabbreviations have been used: ppm for part per million; s for singlet; dfor doublet; t for triplet; q for quartet; b for broad; J for thecouplings expressed in hertz; dd for double doublet.

EXAMPLE 17-Bromo-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR25##

A solution of n-butyllithium (1.6 mol/l) in hexane (93 ml, 0.15 mol) andof anhydrous diethyl ether (200 ml) is cooled to -78° C. under a drynitrogen stream. A solution of 2-bromopyridine (14.3 ml, 0.15 mol) indiethyl ether (100 ml) is added over 1 hour and the mixture is thenstirred for a further 0.5 hour at -78° C.

A solution of7-bromo-3,3-dimethyl-2,3,4,5-tetra-hydro-1-benzoxepin-5-one (13.5 g,0.05 mol) in dry benzene (150 ml) is added over 1 hour at -78° C.Stirring is continued for 1.5 hours at -78° C. and 1 hour at -15° C.Ice-cold water (100 ml) is then added via a dropping funnel andextraction is carried out with diethyl ether. The organic phase iswashed with water and dried over anhydrous sodium sulfate. The solutionis concentrated under reduced pressure (brown oil).

[yellow solid; 14 g; M.p.=124°-128° C.; hexane; 80%]

IR in cm⁻¹ : 3340, 2950, 1595, 1580

¹ H NMR (CDCl₃) in ppm: 8.50 (1H, dd, J=4.5 Hz), 7.20 (6H, m), 5.75 (1H,s), 4.08 (1H, d, J=11 Hz), 3.80 (1H, d, J=11 Hz), 2.34 (1H, d, J=13.5Hz), 1.66 (1H, d, J=13.5 Hz), 1.06 (3H, s), 0.86 (3H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      Br       N    O                                        ______________________________________                                        % Found    58.56    5.28   22.95  4.02                                        % Calculated                                                                             58.63    5.21   22.95  4.02 9.19                                   ______________________________________                                    

By using the same process, the following compounds are prepared.

7-Chloro-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR26##

[flash chromatography: CH₂ Cl₂ ; M.p.=118° C.; hexane; 83%]

IR in cm⁻¹ : 3340, 2950, 1595, 1570.

¹ H NMR (CDCl₃) in ppm: 8.54 (1H, dd, J=1.5 Hz), 7.22 (6H, m), 5.75 (1H,s), 4.11 (1H, d, J=11 Hz), 3.85 (1H, d, J=11 Hz), 2.37 (1H, d, J=13.5Hz), 1.71 (1H, d, J=13.5 Hz), 1.07 (3H, s), 0.88 (3H, s).

7-Fluoro-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR27##

[M.p.=110° C.; hexane; 64%]

IR in cm⁻¹ : 3320, 2960, 1595, 1580.

¹ H NMR (CDCl₃) in ppm: 8.50 (1H, dd, J=4.5 Hz), 7.05 (6H, m), 5.65 (1H,s), 4.05 (1H, d, J=12 Hz), 3.80 (1H, d, J=12 Hz), 2.42 (1H, d, J=14 Hz),1.75 (1H, d, J=14 Hz), 1.09 (3H, s), 0.88 (3H, s).

3,3-Dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR28##

[chromatography with silica gel and CH₂ Cl₂ ; oil; 87%]

IR in cm⁻¹ : 3360, 2950, 1595, 1580

¹ H NMR (CDCl₃) in ppm: 8.46 (1H, dd, J=4.5 Hz), 7.15 (6H, m), 5.75 (1H,m), 4.15 (1H, d, J=12 Hz), 3.85 (1H, d, J=12 Hz), 2.37 (1H, d, J=13.5Hz), 1.70 (1H, d, J=13.5 Hz), 1.10 (3H, s), 0.92 (3H, s).

3,3,7-Trimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR29##

[M.p.=126° C.; hexane; 66%]

IR in cm⁻¹ : 3310, 2960, 1595, 1575, 1500

¹ H NMR (CDCl₃) in ppm: 8.52 (1H, dd, J=4.5 Hz), 7.05 (6H, m), 5.63 (1H,m), 4.07 (1H, d, J=11 Hz), 3.85 (1H, d, J=11 Hz), 2.41 (1H, d, J=13.5Hz), 2.10 (3H, s), 1.74 (1H, d, J=13.5 Hz), 1.09 (3H, s), 0.88 (3H, s).

7-Ethyl-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR30##

[chromatography with silica gel and dichloromethane/methanol: 98/2;M.p.=84° C.; hexane; 76% ]

IR in cm⁻¹ : 3350, 2970, 1595, 1565, 1500

7-Isopropyl-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR31##

[M.p.=72° C.; crystallizes from pentane; 72%]

IR in cm⁻¹ : 3310, 2960, 1585, 1495

¹ H NMR (CDCl₃) in ppm: 8.50 (1H, m), 7.53 (1H, m), 6.91 (5H, m), 5.63(1H, s), 4.10 (1H, d, J=11 Hz), 3.82 (1H, d, J=11 Hz), 2.68 (1H, m),2.38 (1H, d, 13.5 Hz), 1.70 (1H, d, 13.5 Hz), 1.02 (12H, m).

3-Dimethyl-7-(1-methylpropyl)-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR32##

[chromatography with silica gel and dichloromethane/heptane: 80/20; 33%]

IR in cm⁻¹ : 3370, 2970, 1600, 1580, 1500

¹ H NMR (CDCl₃) in ppm: 8.46 (1H, m), 7.05 (6H, m), 5.65 (1H, s), 4.09(1H, d, J=11 Hz), 3.79 (1H, d, J=11 Hz), 2.35 (1H, d, J=13.5 Hz), 2.22(1H, m), 1.65 (1H, d, J=13.5 Hz), 1.06 (14H, m).

7-Methoxy-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1benzoxepin-5-ol##STR33##

[chromatography with silica gel and dichloromethane/methanol: 95/5; M.p.98° C.; hexane; 68%]

IR in cm⁻¹ : 3270, 2970, 1595, 1575, 1500

¹ H NMR (CDCl₃) in ppm: 8.50 (1H, dd, J=4.5 Hz), 7.05 (6H, m), 5.53 (1H,s), 3.89 (2H, s), 3.55 (3H, s), 2.42 (1H, d, J=13.5 Hz), 1.76 (1H, d,J=13.5 Hz), 1.04 (3H, s), 0.80 (3H, s).

3,3-Dimethyl-5-(2-pyridyl)-7-trifluoromethoxy-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR34##

[chromatography with silica gel and dichloromethane; M.p.=76° C.;heptane; 62%]

IR in cm⁻¹ : 3290, 2950, 1590, 1485

¹ H NMR (CDCl₃) in ppm: 8.52 (1H, m), 7.13 (6H, m), 5.78 (1H, s), 4.16(1H, d, J=11 Hz), 3.84 (1H, d, J=11 Hz), 2.39 (1H, d, J=13.5 Hz), 1.73(1H, d, J=13.5 Hz), 1.10 (3H, s), 0.90 (3H, s).

3,3-Dimethyl-7-methylthio-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-o##STR35##

[B.p.₀.2 mm Hg =180° C.; 69%]

IR in cm⁻¹ : 3340, 2970, 1595, 1575

¹ H NMR (CDCl₃) in ppm: 8.53 (1H, m), 7.23 (6H, m), 5.70 (1H, s), 4.10(1H, d, J=11 Hz), 3.81 (1H, d, J=11 Hz), 2.36 (1H, d, J=14 Hz), 2.25(3H, s), 1.71 (1H, d, J=14 Hz), 1.09 (3H, s), 0.89 (3H, s).

3,3-Dimethyl-7-phenyl-5-(2-pyridyl)-2,3,4,5-benzoxepin-5-ol ##STR36##

[chromatography with silica gel and dichloromethane; M.p.=140°-150° C.;heptane; 95%]

IR in cm⁻¹ : 3290, 2930, 1600

¹ H NMR (CDCl₃) in ppm: 8.50 (1H, m), 7.22 (11H, m), 5.82 (1H, m), 4.20(1H, d, J=11 Hz), 3.89 (1H, d, J=11 Hz), 2.41 (1H, d, J=14 Hz), 1.75(1H, d, J=14 Hz), 1.13 (3H, s), 0.95 (3H, s).

8-Bromo-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR37##

[chromatography with silica gel and dichloromethane; M.p.=110° C.;crystallization from hexane; 85%]

IR in cm⁻¹ : 3300, 2950, 1595, 1565, 1480

¹ H NMR (CDCl₃) in ppm: 8.55 (1H, m), 7.55 (1H, dd, J=1.5 Hz, J=7.5 Hz),7.07 (4H, m), 6.57 (1H, d, J=8 Hz), 5.87 (1H, m), 4.20 (1H, d, J=11 Hz),3.90 (1H, d, 11 Hz), 2.37 (1H, d, J=13.5 Hz), 1.71 (1H, d, J=13.5 Hz),1.12 (3H, s), 0.92 (3H, s).

6,8-Dichloro-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR38##

[M.p.=156° C.; heptane; 76%]

IR in cm⁻¹ : 3350, 3060, 2950, 1585, 1550

¹ H NMR (CDCl₃) in ppm: 8.49 (1H, m), 7.12 (5H, m), 5.81 (1H, s), 4.16(1H, d, J=10.5 Hz), 3.92 (1H, d, J=10.5 Hz), 2.12 (1H, d, J=14 Hz), 1.52(1H, d, J=14 Hz), 1.19 (3H, s), 0.98 (3H, s).

7,8-Dichloro-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR39##

[M.p.=128° C.; hexane; 73%]

IR in cm⁻¹ : 3350, 2970, 1595, 1585, 1550

¹ H NMR (CDCl₃) in ppm: 8.51 (1H, m), 7.35 (3H, m), 7.08 (1H, s), 6.83(1H, s), 5.77 (1H, s), 4.12 (1H, d, J=11 Hz), 3.83 (1H, d, J=11 Hz),2.34 (1H, d, J=13.5 Hz), 1.70 (1H, d, J=13.5 Hz), 1.06 (3H, s), 0.88(3H, s).

7,9-Dichloro-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR40##

[chromatography with silica gel and dichloromethane; 83%]

IR in cm⁻¹ : 3300, 2950, 1590, 1570, 1560

¹ H NMR (CDCl₃) in ppm: 8.52 (1H, m), 7.25 (5H, m), 5.70 (1H, s), 4.00(2H, s), 2.39 (1H, d, J=14 Hz), 1.76 (1H, d, J=14 Hz), 1.05 (3H, s),0.86 (3H, s).

8,9-Dichloro-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR41##

[yellow oil; 37%]

IR in cm⁻¹ : 3300, 2960, 1595, 1585, 1560

¹ H NMR (CDCl₃) in ppm: 8.52 (1H, m), 7.15 (5H, m), 5.76 (1H, s), 4.07(2H, s), 2.37 (1H, d, J=13.5 Hz), 1.72 (1H, d, J=13.5 Hz), 1.10 (3H, s),0.90 (3H, s).

7,8-Difluoro-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR42##

[M.p.=93° C.; crystallizes from pentane; 61%]

IR in cm⁻¹ : 3320, 2990, 1600, 1575, 1505

¹ H NMR (CDCl₃) in ppm: 8.52 (1H, m), 7.61 (1H, m), 6.84 (4H, m), 5.71(1H, s), 4.08 (1H, d, J=11 Hz), 3.83 (1H, d, J=11 Hz), 2.35 (1H, d,J=13.5 Hz), 1.70 (1H, d, J=13.5 Hz), 1.06 (3H, s), 0.87 (3H, s).

8-Chloro-7-fluoro-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR43##

[M.p.=100° C.; hexane; 77%]

IR in cm⁻¹ : 3310, 2965, 1595, 1585, 1485

¹ H NMR (CDCl₃) in ppm: 8.55 (1H, m), 7.61 (1H, m), 7.10 (3H, m), 6.63(1H, d), 5.70 (1H, s), 4.08 (1H, d, J=6 Hz), 3.83 (1H, d, J=6 Hz), 2.40(1H, d, J=13.5 Hz), 1.75 (1H, d, J=13.5 Hz), 1.08 (3H, s), 0.86 (3H, s).

9-Ethyl-7-fluoro-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR44##

[M.p.=100° C.; crystallizes from pentane; 68%]

IR in cm⁻¹ : 3260, 2965, 1590

¹ H NMR (CDCl₃) in ppm: 8.53 (1H, m), 7.04 (5H, m), 5.45 (1H, s), 3.85(2H, s), 2.70 (2H, q), 2.40 (1H, d, J=13.5 Hz), 1.75 (1H, d, J=13.5 Hz),1.19 (3H, t), 1.02 (3H, s), 0.78 (3H, s).

7,8-Dimethoxy-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR45##

[chromatography with silica gel and dichloromethane/methanol: 98/2;M.p.=90° C.; crystallization from heptane; 63%]

IR in cm⁻¹ : 3370, 2950, 1610, 1590, 1505

¹ H NMR (CDCl₃) in ppm: 8.52 (1H, m), 7.56 (1H, m), 7.06 (3H, m), 6.54(1H, s), 6.31 (1H, s), 5.50 (1H, m), 4.08 (1H, d, J=10 Hz), 3.81 (3H,s), 3.80 (1H, d, J=10 Hz), 3.55 (3H, s), 2.38 (1H, d, J=13 Hz), 1.73(1H, d, J=13 Hz), 1.08 (3H, s), 0.85 (3H, s).

7-Bromo-3,3,8-trimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR46##

[chromatography with silica gel and dichloromethane; M.p.=147° C.;crystallizes from hexane; 63%]

IR in cm⁻¹ : 3360, 2970, 1595, 1570, 1540

¹ H NMR (CDCl₃) in ppm: 8.54 (1H, m), 7.60 (1H, m), 7.05 (4H, m), 5.70(1H, m), 4.10 (1H, d, J=11 Hz), 3.81 (1H, d, 11 Hz), 2.35 (1H, d, J=13.5Hz), 2.27 (3H, s), 1.69 (1H, d, J=13.5 Hz), 1.07 (3H, s), 0.88 (3H, s).

8-Bromo-3,3,7-trimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR47##

[chromatography with silica gel and dichloromethane; m.p.=129° C.;crystallizes from hexane; 70%]

IR in cm⁻¹ : 3320, 2950, 1595, 1560

¹ H NMR (CDCl₃) in ppm: 8.52 (1H, m), 7.55 (1H, m), 7.14 (1H, s), 7.04(2H, m), 6.62 (1H, s), 5.64 (1H, s), 4.05 (1H, d, J=11 Hz), 3.80 (1H, d,J=11 Hz), 2.32 (1H, d, J=13.5 Hz), 2.11 (3H, s), 1.67 (1H, d, J=13.5Hz), 1.05 (3H, s), 0.66 (3H, s).

3,3-Dimethyl-5-(2-pyridyl)-2,3,4,5,7,8,9,10-octahydro-1-naphth[2,3-b]oxepin-5-ol ##STR48##

[chromatography with silica gel and dichloromethane; M.p.=134° C.; 67%]

IR in cm⁻¹ : 3330, 3060, 2930, 1620, 1595, 1570, 1500

¹ H NMR (CDCl₃) in ppm: 8.50 (1H, m), 7.54 (1H, m), 7.08 (2H, m), 6.66(1H, s), 6.50 (1H, s), 5.50 (1H, s), 4.02 (1H, d, J=10.5 Hz), 3.77 (1H,d, J=10.5 Hz), 2.56 (4H, m), 2.36 (1H, d, J=13.5 Hz), 1.74 (5H, m), 1.05(3H, s), 0.83 (3H, s).

3,3-Dimethyl-5-(2-pyridyl)-7-trifluoromethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR49##

[chromatography with silica gel and dichloromethane; M.p.=116° C.;crystallization from isooctane; 29%]

IR in cm⁻¹ : 3330, 2970, 1625, 1600, 1580, 1505

¹ H NMR (CDCl₃) in ppm: 8.50 (1H, dd, J=4.5 Hz), 7.25 (6H, m), 5.90 (1H,s), 4.22 (1H, d, J=11 Hz), 3.90 (1H, d, J=11 Hz), 2.35 (1H, d, J=13.5Hz), 1.72 (1H, d, J=13.5 Hz), 1.10 (3H, s), 0.92 (3H, s).

3,3-Dimethyl-5-(2-pyridyl)-8-trifluoromethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR50##

[chromatography with silica gel and dichloromethane; M.p.=78° C.; 31%]

IR in cm⁻¹ : 3330, 2970, 1595, 1575, 1500

¹ H NMR (CDCl₃) in ppm: 8.55 (1H, dd, J=4.5 Hz), 7.25 (6H, m), 5.94 (1H,s), 4.22 (1H, d, J=11 Hz), 3.90 (1H, d, J=11 Hz), 2.40 (1H, d, J=14 Hz),1.72 (1H, d, J=14 Hz), 1.12 (3H, s), 0.95 (3H, s).

3,3-Dimethyl-5-(2-pyridyl)-7-pentafluoroethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR51##

[chromatography with silica gel and dichloromethane; 42%]

IR in cm⁻¹ : 3330, 2950, 1620, 1595, 1575, 1500

¹ H NMR (CDCl₃) in ppm: 8.55 (1H, dd, J=4.5 Hz), 7.28 (6H, m), 6.00 (1H,s), 4.33 (1H, d, J=11 Hz), 3.94 (1H, d, J=11 Hz), 2.38 (1H, d, J=14 Hz),1.75 (1H, d, J=14 Hz), 1.15 (3H, s), 0.97 (3H, s).

8-Bromo-3,3-dimethyl-1-(2-pyridyl)-2,3,4,5-tetrahydro-1H-benzo[f]cyclohepten-1-ol ##STR52##

[chromatography with silica gel and dichloromethane; oil; 78%]

IR in cm⁻¹ : 3340, 2960, 1590, 1570

¹ H NMR (CDCl₃) in ppm: 8.50 (1H, m), 7.54 (1H, m), 7.04 (5H, m), 5.39(1H, s), 2.90 (2H, m), 2.32 (1H, d, J=14 Hz), 1.77 (1H, d, J=14 Hz),1.70 (2H, m), 1.02 (6H, m).

7-Bromo-3,3-dimethyl-5-(3-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR53##

By using the same process as above and the use of 3-bromopyridinereplacing 2-bromopyridine.

[M.p.=170° C.; ethyl acetate; 46%]

IR in cm⁻¹ : 3120, 2950, 1585, 1475

¹ H NMR (CDCl₃) in ppm: 8.37 (2H, m), 7.14 (4H, m), 6.88 (1H, d, J=9Hz), 3.76 (2H, s), 3.74 (1H, m), 2.35 (1H, d, J=13.5 Hz), 2.00 (1H, d,J=13.5 Hz), 1.01 (3H, s), 0.62 (3H, s).

7,8-Dichloro-3,3-dimethyl-5-(3-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR54##

M.p.=166° C.; crystallization from heptane; 44%]

IR in cm⁻¹ : 3100, 2930, 1595, 1585

¹ H NMR (CDCl₃) in ppm: 8.41 (2H, m), 7.34 (4H, m), 3.76 (3H, s), 2.35(1H, d, J=13.5 Hz); 2.00 (1H, d, J=13.5 Hz), 1.00 (3H, s), 0.61 (3H, s).

EXAMPLE 2 7-Bromo-5-methoxy-3,3-dimethyl-5-(2-pyridyl)-1-benzoxepine##STR55##

A solution of 7-bromo-3,3-dimethyl-5-(2-pyridyl)-benzoxepin-5-ol (5 g,0.014 mol) in anhydrous DMF (50 ml) is added dropwise to a suspension ofsodium hydride (50% dispersed in oil, 0.8 g, 0.0168 mol) in anhydrousDMF (25 ml), the temperature rises to 88° C., stirring is continued for1 hour and the reaction mixture is maintained at 80° C. A solution ofmethyl iodide (1.9 g, 0.014 mol) in anhydrous DMF (10 ml) is then addeddropwise at 25° C.

The whole mixture is stirred for 16 hours at 25° C. and then hydrolysedwith 600 ml of ice-cold water. The paste obtained is dissolved indichloromethane (250 ml). The organic phase is washed with water, driedover anhydrous sodium sulfate and concentrated under reduced pressure.

[pasty product; 5 g; 98%]

IR in cm⁻¹ : 2960, 1590, 1565

¹ H NMR (CDCl₃) in ppm: 8.55 (1H, dd, J=4.5 Hz), 7.33 (6H, m), 3.91 (1H,s), 3.88 (1H, s), 3.16 (3H, s), 2.26 (2H, s), 1.11 (3H, s), 0.43 (3H,s).

EXAMPLE NO. 37-Bromo-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ylacetate ##STR56##

A solution of 7-bromo-3,3-dimethyl-5-(2-pyridyl)-1-benzoxepin-5-ol (5 g,0.014 mol) in anhydrous DMF (50 ml) is added dropwise at 60° C. to asuspension of sodium hydride (50% dispersed in oil, 0.8 g, 0.0168 mol)in anhydrous DMF (25 ml).

The suspension is stirred for 1 hour at 60° C. and then cooled. Acetylchloride (1 g, 0.014 mol) is added dropwise at 25° C. and the stirringis continued at 25° C. for 16 hours. The whole mixture is thenhydrolysed in 600 ml of ice-cold water. The beige paste obtained isdissolved in 200 ml of dichloromethane. The organic phase is washed withwater, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The oil obtained is purified by chromatography withsilica gel and dichloromethane/methanol: 98/2.

[M.p.=140° C.; hexane; 22%]

IR in cm⁻¹ : 2950, 1745, 1590, 1570, 1485

¹ H NMR (CDCl₃) in ppm: 8.50 (1H, dd, J=4.5 Hz), 7.25 (6H, m), 3.78 (2H,s), 2.95 (1H, d, J=13.5 Hz), 2.38 (1H, d, J=13.5 Hz), 2.07 (3H, s), 1.05(3H, s), 0.37 (3H, s).

EXAMPLE NO. 4 7-Bromo-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol ##STR57##

A solution of7-bromo-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol(3.5 g, 0.01 mol) and of 3-chloroperbenzoic acid (2.8 g, 0.016 mol) indichloromethane (50 ml) is stirred for 16 hours at 25° C.

The precipitate formed is filtered. The filtrate is washed with a 5%sodium bisulfite solution, then with a 5% sodium bicarbonate solutionand with water. The organic phase is dried over anhydrous sodium sulfateand concentrated under reduced pressure (thick yellow oil). The productis recrystallized from hexane (2.6 g).

[M.p.=139°-140° C.; hexane]

IR in cm⁻¹ : 3240, 3050, 2950, 1480

¹ H NMR (CDCl₃) in ppm: 8.18 (1H, m), 7.88 (1H, d), 7.13 (5H, m), 6.03(1H, m), 3.81 (1H, m), 3.49 (1H, m), 3.31 (1H, m), 1.94 (1H, d, J=13.5Hz), 0.86 (3H, s), 0.51 (3H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      Br       N    O                                        ______________________________________                                        % Found    56.07    5.02          3.73 13.42                                  % Calculated                                                                             56.05    4.98   21.94  3.85 13.18                                  ______________________________________                                    

By using the same process, the following compounds are prepared.

7-Chloro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol ##STR58##

[M.p.=138°-140° C.; ethyl acetate; 34%]

IR in cm⁻¹ : 3250, 3070, 2950, 1480

¹ H NMR (CDCl₃) in ppm: 8.23 (1H, m), 7.77 (1H, d), 7.11 (5H, m), 6.05(1H, m), 3.82 (1H, m), 3.50 (1H, m), 3.32 (1H, m), 1.93 (1H, d, J=14Hz), 0.85 (3H, s), 0.56 (3H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      Cl       N    O                                        ______________________________________                                        % Found    63.58    5.71   11.04  4.47                                        % Calculated                                                                             63.85    5.67   11.09  4.38 15.01                                  ______________________________________                                    

7-Fluoro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol ##STR59##

[M.p. =110°-112° C.; hexane; 78%]

IR in cm⁻¹ : 3390, 3110, 2950, 1485

¹ H NMR (CDCl₃) in ppm: 8.19 (1H, m), 7.30 (7H, m), 3.80 (1H, m), 3.48(1H, m), 3.34 (1H, m), 1.93 (1H, d, J=14 Hz), 0.85 (6H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      F        N    O                                        ______________________________________                                        % Found    67.14    6.04   6.16   4.53                                        % Calculated                                                                             67.31    5.98   6.26   4.62 15.82                                  ______________________________________                                    

3,3-Dimethyl-5-(2-pyridyl N-oxide)-2,3,4,5-tetrahydro-1-benzoxepin -5-ol##STR60##

[chromatography with silica gel and ethyl acetate/chloroform/methanol;60/30/10; M.p.=127°-128° C.; cyclohexane; 41%]

IR in cm⁻¹ : 3180, 3070, 2950, 1605, 1575, 1480

¹ H NMR (CDCl₃) in ppm: 8.20 (1H, m), 7.75 (1H, m), 7.05 (6H, m), 3.81(1H, m), 3.52 (1H, m), 3.32 (1H, m), 1.97 (1H, d, J=14 Hz), 0.88 (3H,s), 0.60 (3H, s).

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      71.58  6.88       4.85                                           % Calculated 71.56  6.71       4.91 16.82                                     ______________________________________                                    

7-Ethyl-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol ##STR61##

[chromatography with silica gel and dichloromethane/methanol; 98/2;M.p.=123°-125° C.; diisopropyl ether; 23%]

IR in cm⁻¹ : 3230, 3050, 2950, 1615, 1580, 1500

¹ H NMR (CDCl₃) in ppm: 8.20 (1H, m), 7.60 (1H, m), 7.11 (5H, m), 6.50(1H, m), 3.80 (1H, m), 3.50 (1H, m), 3.30 (1H, m), 2.64 (2H, q), 1.93(1H, d, J=13.5 Hz), 1.21 (3H, t), 0.83 (3H, s), 0.54 (3H, s).

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      73.03  7.49       4.57                                           % Calculated 72.82  7.40       4.47 15.32                                     ______________________________________                                    

3,3-Dimethyl-7-(1-methylpropyl)-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol ##STR62##

[chromatography with silica gel and dichloromethane; M.p.=131°-133° C.;diisopropyl ether; 39%]

IR in cm⁻¹ : 3150, 2960, 1610, 1495

¹ H NMR (CDCl₃) in ppm: 8.20 (1H, m), 7.20 (7H, m), 3.77 (1H, d, J=11Hz), 3.48 (1H, d, J=11 Hz), 3.28 (1H, d, J=14 Hz), 2.58 (1H, q), 1.92(1H, d, J=14 Hz), 1.10 (14H, m).

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      73.66  7.97       4.39                                           % Calculated 73.87  7.97       4.10 14.06                                     ______________________________________                                    

7-Methoxy-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol ##STR63##

[chromatography with silica gel and dichloromethane/methanol; 98/2;M.p.=109°-110° C.; isooctane]

IR in cm⁻¹ : 3200, 3080, 2950, 1605, 1495

¹ H NMR (CDCl₃) in ppm: 8.19 (1H, m), 7.15 (7H, m), 3.74 (3H, s), 3.58(3H, m), 1.90 (1H, d, J=13.5 Hz), 0.82 (3H, s), 0.55 (3H, s).

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      68.52  6.55       4.48                                           % Calculated 68.55  6.71       4.44 20.29                                     ______________________________________                                    

3,3-Dimethyl-5-(2-pyridylN-oxide)-7-trifluoromethoxy-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR64##

[chromatography with silica gel and dichloromethane; M.p.=114°-116° C.;heptane; 50%]

IR in cm⁻¹ : 3400, 3130, 3060, 2970, 1490

¹ H NMR (CDCl₃) in ppm: 8.21 (1H, m), 7.64 (1H, m), 7.01 (6H, m), 3.80(1H, d, J=11 Hz), 3.49 (1H, d, J=11 Hz), 3.30 (1H, d, J=14 Hz), 1.91(1H, d, J=14 Hz), 0.84 (3H, s), 0.52 (3H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      F        N    O                                        ______________________________________                                        % Found    58.33    4.95   15.31  3.86                                        % Calculated                                                                             58.53    4.91   15.43  3.79 17.33                                  ______________________________________                                    

3,3-Dimethyl-7-phenyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol ##STR65##

[chromatography with silica gel and methanol; M.p.=175° C.; diisopropylether/ethyl acetate; 50/50; 25%]

IR in cm⁻¹ : 3200, 2960, 1610

¹ H NMR (CDCl₃) in ppm: 8.14 (2H, m), 7.27 (10H, m), 3.85 (1H, d, J=11Hz), 3.55 (1H, d, J=11 Hz), 3.34 (1H, d, J=14 Hz), 2.02 (1H, d, J=14Hz), 0.90 (3H, s), 0.60 (3H, s).

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      76.57  6.37       3.90                                           % Calculated 76.43  6.41       3.88 13.28                                     ______________________________________                                    

7-Bromo-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol ##STR66##

[M.p.=137°-138° C.; ethyl acetate; 20%]

IR in cm⁻¹ : 3090, 2950, 1590, 1560, 1475

¹ H NMR (CDCl₃) in ppm: 8.20 (1H, m), 7.65 (1H, m), 7.62 (1H, d, J=8Hz), 7.03 (5H, m), 3.81 (1H, d, J=11 Hz), 3.50 (1H, d, J=11 Hz), 3.29(1H, d, J=14 Hz), 1.92 (1H, d, J=14 Hz), 0.88 (3H, s), 0.53 (3H, s).

6,8-Dichloro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol ##STR67##

[M.p.=220° C.; ethyl acetate; 35%]

IR in cm⁻¹ : 3065, 2970, 1585, 1550

¹ H NMR (CDCl₃) in ppm: 8.15 (1H, m), 6.92 (5H, m), 4.00 (2H, s), 2.18(2H, s), 1.28 (3H, s), 1.00 (3H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      Cl       N    O                                        ______________________________________                                        % Found    57.54    4.84   20.23  4.04                                        % Calculated                                                                             57.64    4.84   20.02  3.95 13.55                                  ______________________________________                                    

7,8-Dichloro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol ##STR68##

[M.p.=134°-136° C.; diisopropyl oxide; 18%]

IR in cm⁻¹ : 3250, 3050, 2970, 1480

¹ H NMR (CDCl₃) in ppm: 8.21 (1H, m), 7.85 (1H, s), 7.08 (5H, m), 3.80(1H, d, J=11 Hz), 3.38 (2H, m), 1.90 (1H, d, J=14 Hz), 0.88 (3H, s),0.55 (3H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      Cl       N    O                                        ______________________________________                                        % Found    57.80    4.70   19.73  4.02                                        % Calculated                                                                             57.64    4.84   20.02  3.95 13.55                                  ______________________________________                                    

7,9-Dichloro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol ##STR69##

[M.p.=150°-5° C.; diisopropyl ether; 33%]

IR in cm⁻¹ : 3230, 3070, 2970, 1570

¹ H NMR (CDCl₃) in ppm: 8.20 (1H, m), 7.70 (1H, m), 7.09 (4H, m), 3.89(1H, dd, J=1.5 Hz, J=11 Hz), 3.40 (1H, d, J=11 Hz), 3.31 (1H, dd, J=1.5Hz, J=13.5 Hz), 1.82 (1H, d, J=13.5 Hz), 0.81 (3H, s), 0.59 (3H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      Cl       N    O                                        ______________________________________                                        % Found    57.38    4.89   20,02  3.99                                        % Calculated                                                                             57.64    4.84   20.02  3.95 13.55                                  ______________________________________                                    

8-Chloro-7-fluoro-3,3-dimethyl-5-(2-pyridylN-oxide-)2,3,4,5-tetrahydro-1-benzoxepin-5-ol ##STR70##

[M.p.=121°-123° C.; diisopropyl oxide; 24%]

IR in cm⁻¹ : 3290, 3070, 1485

¹ H NMR (CDCl₃) in ppm: 8.23 (1H, m), 7.87 (1H, s), 7.60 (1H, d), 7.08(4H, m), 3.58 (3H, m), 1.90 (1H, d, J=14 Hz), 0.84 (3H, s), 0.55 (3H,s).

    ______________________________________                                        Elemental analysis                                                                     C    H       Cl     F     N    O                                     ______________________________________                                        % Found    60.44  5.30    10.56                                                                              5.69  4.16                                     % Calculated                                                                             60.45  5.07    10.50                                                                              5.63  4.15 14.21                               ______________________________________                                    

7,8-Dimethoxy-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrohydro-1-benzoxepin-5-ol ##STR71##

[chromatography with silica gel and dichloromethane/methanol; 98/2;M.p.=174° C.; ethyl acetate]

IR in cm⁻¹ : 3220, 3090, 2970, 1615, 1510

¹ H NMR (CDCl₃) in ppm: 8.22 (1H, m), 7.18 (4H, m), 6.62 (1H, s), 3.87(3H, s), 3.80 (3H, s), 3.76 (1H, d, J=10 Hz), 3.50 (1H, d, J=10 Hz),3.29 (1H, d, J=13 Hz), 1.92 (1H, d, J=13 Hz), 0.87 (3H, s), 0.55 (3H,s).

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      66.35  6.87       4.20                                           % Calculated 66.07  6.71       4.06 23.16                                     ______________________________________                                    

3,3-Dimethyl-5-(2-pyridylN-oxide)-7-trifluoromethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR72##

[M.p.=106°-107° C.; hexane; 76%]

IR in cm⁻¹ : 3400, 3110, 2950, 1615, 1590, 1500, 1480

¹ H NMR (CDCl₃) in ppm: 8.05 (2H, m), 7.13 (6H, m), 3.80 (1H, m), 3.50(1H, m), 3.29 (1H, m), 1.95 (1H, d, J=13.5 Hz), 0.86 (3H, s), 0.54 (3H,s).

    ______________________________________                                        Elemental analysis                                                                     C      H      F        N    O                                        ______________________________________                                        % Found    61.40    5.08   16.01  4.01                                        % Calculated                                                                             61.18    5.14   16.13  3.96 13.58                                  ______________________________________                                    

3,3-Dimethyl-5-(2-pyridylN-oxide)-8-trifluoromethyl-2,3,4,5-tetrahydro-1-benzoxepin-5-ol##STR73##

[chromatography with silica gel and dichloromethane/methanol; 98/2;M.p.=102°-105° C.; cyclohexane; 27%]

IR in cm⁻¹ : 3400, 3050, 2950, 1585, 1480

¹ H NMR (CDCl₃) in ppm: 8.20 (1H, m), 7.37 (7H, m), 3.86 (1H, m), 3.55(1H, m), 3.32 (1H, m), 1.95 (1H, d, J=14 Hz), 0.88 (3H, s), 0.56 (3H,s).

7-Bromo-5-methoxy -3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepine ##STR74##

[M.p.=178°-180° C.; ethyl acetate; 33%]

IR in cm⁻¹ : 2960, 1595, 1560, 1480

¹ H NMR (CDCl₃) in ppm: 8.06 (1H, m), 7.14 (6H, m), 3.98 (1H, d, J=11Hz), 3.70 (1H, d, J=11 Hz), 3.33 (1H, d, J=14 Hz), 3.05 (3H, s), 1.61(1H, d, J=14 Hz), 1.11 (3H, s), 0.95 (3H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      Br       N    O                                        ______________________________________                                        % Found    56.96    5.50   21.10  3.58                                        % Calculated                                                                             57.15    5.33   21.13  3.70 12.69                                  ______________________________________                                    

EXAMPLE NO. 5 7-Bromo-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-yl acetate ##STR75##

[M.p.=145°-147° C.; isooctane/ethyl acetate: 80-20%]

IR in cm⁻¹ : 2950, 1730, 1605, 1480

¹ H NMR (CDCl₃) in ppm: 8.05 (1H, m), 7.17 (6H, m), 3.58 (3H, m), 2.19(3H, s), 2.07 (1H, d, J=14 Hz), 0.93 (3H, s), 0.60 (3H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      Br       N    O                                        ______________________________________                                        % Found    56.20    5.05   19.75  3.40                                        % Calculated                                                                             56.17    4.96   19.67  3.45 15.75                                  ______________________________________                                    

7-Bromo-4,5-epoxy-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine ##STR76##

[chromatography with silica gel and ethyl acetate; M.p.=186°-187° C.;ethanol; 20%]

IR in cm⁻¹ : 3060, 2970, 1560, 1480

¹ H NMR (CDCl₃) in ppm: 8.05 (1H, m), 7.22 (6H, m), 3.75 (2H, s), 2.98(1H, s), 1.46 (3H, s), 1.17 (3H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      Br       N    O                                        ______________________________________                                        % Found    56.14    4.51   22.27  3.76 13.07                                  % Calculated                                                                             56.37    4.45   22.06  3.87 13.26                                  ______________________________________                                    

7-Bromo-3,3-dimethyl-5-(3-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol ##STR77##

[M.p.=200° C.; ethanol; 38%]

IR in cm⁻¹ : 3180, 2950, 1595, 1560, 1485

¹ H NMR (DMSO) in ppm: 8.07 (2H, m), 7.14 (5H, m), 6.31 (1H, s), 3.78(2H, s), 2.30 (1H, d, J=13.5 Hz), 1.88 (1H, d, J=13 Hz), 0.94 (3H, s),0.69 (3H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      Br       N    O                                        ______________________________________                                        % Found    56.03    5.03   21.71  3.85                                        % Calculated                                                                             56.05    4.98   21.94  3.85 13.18                                  ______________________________________                                    

7,8-Dichloro-3,3-dimethyl-5-(3-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol ##STR78##

[M.p.=226°-228° C.; isopropanol; 23%]

IR in cm⁻¹ : 3160, 2950, 1590

¹ H NMR (DMSO) in ppm: 8.05 (2H, m), 7.17 (4H, m), 6.32 (1H, s), 3.81(2H, s), 2.30 (1H, d, J=14 Hz), 1.86 (1H, d, J=14 Hz), 0.96 (3H, s),0.71 (3H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      Cl       N    O                                        ______________________________________                                        % Found    57.75    5.12   19.84  4.06                                        % Calculated                                                                             57.64    4.84   20.02  3.95 13.55                                  ______________________________________                                    

EXAMPLE NO. 67-Bromo-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine ##STR79##

A solution of7-bromo-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepin-5-ol(13.9 g, 0.04 mol) and of concentrated sulfuric acid (3.3 ml ofcommercial solution) in benzene (170 ml) is heated for 3 hours atboiling with removal of water.

The solution is washed, at 25° C., with a 1% sodium hydroxide solutionand then with water. The organic phase is dried over anhydrous sodiumsulfate and concentrated under reduced pressure.

[13.2 g; M.p.=113°-114° C.; hexane; 70%]

IR in cm⁻¹ : 2950, 1580, 1560, 1480

¹ H NMR (CDCl₃) in ppm: 8.62 (1H, m), 7.30 (6H, m), 5.90 (1H, s), 3.93(2H, s), 1.20 (6H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      Br       N    O                                        ______________________________________                                        % Found    61.61    4.96   24.03  4.31                                        % Calculated                                                                             61.83    4.88   24.20  4.24 4 85                                   ______________________________________                                    

By using the same process, the following compounds are prepared.

7Chloro-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine ##STR80##

[M.p.=100° C.; hexane; 79%]

IR in cm⁻¹ : 2960, 1585, 1565, 1490

¹ H NMR (CDCl₃) in ppm: 8.62 (1H, m), 7.28 (6H, m), 5.92 (1H, s), 3.91(2H, s), 1.15 (6H, s).

7-Fluoro-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine ##STR81##

[thick yellow oil; 38%]

IR in cm⁻¹ : 2970, 1590, 1565, 1495

¹ H NMR (CDCl₃) in ppm: 8.55 (1H, m), 7.02 (6H, m), 5.89 (1H, s), 3.90(2H, s), 1.16 (6H, s).

3,3-Dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine ##STR82##

[oil; 98%]

IR in cm⁻¹ : 2960, 1590, 1565, 1495

¹ H NMR (CDCl₃) in ppm: 8.56 (1H, m), 7.20 (7H, m), 5.83 (1H, s), 3.94(2H, s), 1.18 (6H, s).

3,3,7-Trimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine ##STR83##

IR in cm⁻¹ : 2960, 1590, 1565, 1500

¹ H NMR (CDCl₃) in ppm: 8.58 (1H, m), 7.10 (6H, m), 5.83 (1H, s), 3.91(2H, s), 2.10 (3H, s), 1.18 (6H, s).

7-Ethyl-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine ##STR84##

[yellow oil; 97%]

IR in cm⁻¹ : 2960, 1590, 1565, 1500

¹ H NMR (CDCl₃) in ppm: 8.58 (1H, m), 7.14 (6H, m), 5.84 (1H, s), 3.91(2H, s), 2.40 (2H, q), 1.16 (6H, s), 1.03 (3H, t).

7-Isopropyl-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine##STR85##

[yellow oil; 98%]

IR in cm⁻¹ : 2960, 1585, 1495

¹ H NMR (CDCl₃) in ppm: 8.59 (1H, m), 7.64 (1H, m), 6.90 (5H, m), 5.84(1H, s), 3.91 (2H, s), 2.68 (1H, m), 1.10 (12H, m).

3,3-Dimethyl-7-(1-methylpropyl)-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine##STR86##

[yellow oil; 77%]

IR in cm⁻¹ : 2965, 1585, 1565, 1500

¹ H NMR (CDCl₃) in ppm: 8.59 (1H, m), 7.29 (5H, m), 6.54 (1H, s), 5.86(1H, s), 3.92 (2H, s), 2.31 (1H, m), 1.09 (14H, m).

7-Methoxy-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine ##STR87##

[M.p.=80° C.; 78%]

IR in cm⁻¹ : 2960, 1585, 1565, 1495

¹ H NMR (CDCl₃) in ppm: 8.54 (1H, m), 7.00 (6H, m), 5.85 (1H, s), 3.88(2H, s), 3.50 (3H, s), 1.03 (6H, s).

3-Dimethyl-5-(2-pyridyl)-7-trifluoromethoxy-2,3-dihydro-1-benzoxepine##STR88##

[M.p.=112° C.; cyclohexane; 85%]

IR in cm⁻¹ : 3070, 3045, 2960, 1585, 1560

¹ H NMR (CDCl₃) in ppm: 8.59 (1H, m), 7.66 (1H, m), 7.13 (4H, m), 6.59(1H, s), 5.91 (1H, s), 3.91 (2H, s), 1.17 (6H, s).

3,3-Dimethyl-7-methylthio-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine##STR89##

[B.p.₀.8 mm Hg =140°-160° C.; 60%]

IR in cm⁻¹ : 2970, 2870, 1585, 1560

¹ H NMR (CDCl₃) in ppm: 8.58 (1H, m), 7.65 (1H, m), 6.96 (5H, m), 5.87(1H, s), 3.90 (2H, s), 2.22 (3H, s), 1.19 (6H, s).

3,3-Dimethyl-7-phenyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine ##STR90##

[M.p.=115°-120° C.; heptane; 42%]

IR in cm⁻¹ : 3050, 2950, 1600

¹ H NMR (CDCl₃) in ppm: 8.60 (1H, m), 7.30 (11H, m), 5.91 (1H, s), 3.99(2H, s), 1.21 (6H, s).

8-Bromo-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine ##STR91##

[yellow oil; 90%]

IR in cm⁻¹ : 3060, 2950, 1585, 1555, 1485, 1465

¹ H NMR (CDCl₃) in ppm: 8.59 (1H, m), 7.62 (1H, dd), 7.11 (4H, m), 6.61(1H, d, J=8 Hz), 5.90 (1H, s), 3.95 (2H, s), 1.18 (6H, s).

7-Cyano-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine ##STR92##

[chromatography with silica gel and cyclohexane/chloroform/methanol;56/33/11; M.p.=155°-157° C., ethyl acetate; 57%]

IR in cm⁻¹ : 2960, 2220, 1590, 1570, 1495

¹ H NMR (CDCl₃) in ppm: 8.55 (1H, m), 7.37 (6H, m), 5.90 (1H, s), 3.95(2H, s), 1.20 (6H, s).

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      78.06  5.94       10.14                                          % Calculated 78.23  5.84       10.14                                                                              5.79                                      ______________________________________                                    

8-Cyano-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine ##STR93##

[chromatography with silica gel and dichloromethane; M.p.=132° C.;crystallization from heptane; 30%]

IR in cm⁻¹ : 2950, 2210, 1585, 1565, 1540, 1500

¹ H NMR (CDCl₃) in ppm: 8.56 (1H, m), 7.66 (1H, m), 7.16 (4H, m), 6.83(1H, d, J=8 Hz), 6.01 (1H, s), 3.95 (2H, s), 1.19 (6H, s),

3,3-Dimethyl-5-(2-pyridyl)-7-trifluoromethyl-2,3-dihydro-1-benzoxepine##STR94##

[M.p.=90° C.; isooctane; 60%]

IR in cm⁻¹ : 2960, 1585, 1565, 1500

3,3-Dimethyl-5-(2-pyridyl)-8-trifluoromethyl-2,3-dihydro-1-benzoxepine##STR95##

[oil; 85%]

IR in cm⁻¹ : 2960, 1585, 1565, 1500

¹ H NMR (CDCl₃) in ppm: 8.60 (1H, m), 7.34 (6H, m), 6.00 (1H, s), 3.98(2H, s), 1.19 (6H, s).

3,3-Dimethyl-5-(2-pyridyl)-7-pentafluoroethyl-2,3-dihydro-1-benzoxepine##STR96##

IR in cm⁻¹ : 2960, 1590, 1565, 1500

6,8-Dichloro-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine##STR97##

[oil]

IR in cm⁻¹ : 2960, 1585, 1545

¹ H NMR (CDCl₃) in ppm: 8.47 (1H, m), 7.22 (5H, m), 6.50 (1H, s), 4.05(2H, s), 1.10 (6H, s).

7,8-Dichloro-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine##STR98##

[M.p.=98° C.; hexane; 81%]

IR in cm⁻¹ : 2960, 1580, 1475

¹ H NMR (CDCl₃) in ppm: 8.58 (1H, m), 7.40 (5H, m), 5.88 (1H, s), 3.90(2H, s), 1.15 (6H, s).

7,9-Dichloro-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine##STR99##

[M.p.=124° C.; heptane; 66%]

IR in cm⁻¹ : 2970, 1585, 1470

¹ H NMR (CDCl₃) in ppm: 8.59 (1H, m), 7.45 (4H, m), 6.62 (1H, d, J=1.5Hz), 5.95 (1H, s), 4.00 (2H, s), 1.21 (6H, s).

8,9-Dichloro-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine##STR100##

[M.p.=112° C.; heptane; 55%]

IR in cm⁻¹ : 2970, 1580, 1475

¹ H NMR (CDCl₃) in ppm: 8.62 (1H, m), 7.67 (1H, m), 7.15 (2H, m), 6.92(1H, d, J=8 Hz), 6.57 (1H, d, J=8 Hz), 5.92 (1H, s), 4.02 (2H, s), 1.22(6H, s).

7,8-Difluoro-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine##STR101##

[M.p.=86° C.; crystallization from pentane; 86%]

IR in cm⁻¹ : 3070, 2970, 1585, 1510

¹ H NMR (CDCl₃) in ppm: 8.58 (1H, m), 7.68 (1H, m), 6.85 (4H, m), 5.85(1H, s), 3.93 (2H, s), 1.20 (6H, s).

8-Chloro-7-fluoro-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine##STR102##

[M.p.=86° C.; 94%]

IR in cm⁻¹ : 2950, 1585, 1560, 1485

¹ H NMR (CDCl₃) in ppm: 8.63 (1H, m), 7.68 (1H, m), 7.18 (3H, m), 6.55(1H, d), 5.90 (1H, s), 3.92 (2H, s), 1.15 (6H, s).

9-Ethyl-7-fluoro-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine##STR103##

[chromatography with silica gel and dichloromethane; 95%]

IR in cm⁻¹ : 2950, 1585

¹ H NMR (CDCl₃) in ppm: 8.60 (1H, m), 7.64 (1H, m), 7.15 (2H, m), 6.70(1H, dd, J=2 Hz, J=8 Hz), 6.30 (1H, dd, J=2 Hz, J=10 Hz), 5.90 (1H, s),3.90 (2H, s), 2.69 (2H, q), 1.20 (9H, m).

7,8-Dimethoxy -3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine##STR104##

[M.p.=86° C.; 57%]

IR in cm⁻¹ : 2950, 1605, 1580, 1515

¹ H NMR (CDCl₃) in ppm: 8.61 (1H, m), 7.63 (1H, m), 7.17 (2H, m), 6.59(1H, s), 6.25 (1H, s), 5.76 (1H, s), 3.92 (2H, s), 3.56 (3H, s), 3.50(3H, s), 1.16 (6H, s).

7-Cyano-3,3,8-trimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine##STR105##

[chromatography with silica gel and dichloromethane; M.p.=171° C.,toluene; 32%]

IR in cm⁻¹ : 3060, 2970, 2220, 1610, 1585, 1560, 1495

¹ H NMR (CDCl₃) in ppm: 8.59 (1H, m), 7.69 (1H, m), 7.19 (2H, m), 7.00(1H, s), 6.90 (1H, s), 5.85 (1H, s), 3.95 (2H, s), 2.41 (3H, s), 1.19(6H, s).

8-Cyano-3,3,7-trimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine##STR106##

[M.p.=136° C.; hexane; 40%]

IR in cm⁻¹ : 3070, 2980, 2230, 1590, 1500

¹ H NMR (CDCl₃) in ppm: 8.56 (1H, m), 7.66 (1H, m), 7.17 (1H, s), 7.14(2H, m), 6.62 (1H, s), 5.96 (1H, s), 3.90 (2H, s), 2.27 (3H, s), 1.18(6H, s).

3,3-Dimethyl-5-(2-pyridyl)-2,3,7,8,9,10-hexahydro-1-naphth[2,3-b]oxepine##STR107##

[M.p.=75° C.; crystallization from hexane; 88%]

IR in cm⁻¹ : 2930, 1610, 1580, 1560, 1500

¹ H NMR (CDCl₃) in ppm: 8.56 (1H, m), 7.60 (1H, m), 7.17 (2H, m), 6.71(1H, s), 6.40 (1H, s), 5.75 (1H, s), 3.90 (2H, s), 2.56 (4H, m), 1.70(4H, m), 1.14 (6H, s).

8-Cyano-3,3-dimethyl-1-(2-pyridyl)-4,5-dihydro-3H-benzo[f]cycloheptene##STR108##

[chromatography with silica gel and ethyl acetate/hexane: 25/75 mixture;M.p.=120° C.; diisopropyl ether; 31%]

IR in cm⁻¹ : 2960, 2915, 2230, 1585, 1560

¹ H NMR (CDCl₃) in ppm: 8.55 (1H, m), 7.62 (1H, m), 7.20 (5H, m), 6.30(1H, s), 2.80 (2H, m), 1.88 (2H, m), 0.95 (6H, m).

7-Bromo-3,3-dimethyl-5-(3-pyridyl)-2,3-dihydro-1-benzoxepine ##STR109##

[M.p.=116° C.; heptane; 73%]

IR in cm⁻¹ : 2950, 1560, 1485, 1465

¹ H NMR (CDCl₃) in ppm: 8.51 (2H, m), 7.35 (3H, m), 6.88 (2H, m), 5.74(1H, s), 3.91 (2H, s), 1.17 (6H, s).

7-Cyano-3,3-dimethyl-5-(3-pyridyl)-2,3-dihydro-1-benzoxepine ##STR110##

[chromatography with silica gel and cyclohexane/chloroform/methanolmixture: 56/33/11; M.p.=150° C.; heptane; 38%]

IR in cm⁻¹ : 3090, 2980, 2250, 1600, 1570, 1500

¹ H NMR (CDCl₃) in ppm: 8.46 (2H, m), 7.18 (5H, m), 5.79 (1H, s), 3.95(2H, s), 1.18 (6H, s).

7,8-Dichloro-3,3-dimethyl-5-(3-pyridyl)-2,3-dihydro-1-benzoxepine##STR111##

[M.p.=112° C.; diisopropyl ether; 36%]

IR in cm⁻¹ : 3020, 2970, 1590, 1565, 1540

¹ H NMR (CDCl₃) in ppm: 8.54 (2H, m), 7.35 (2H, m), 7.10 (1H, s), 6.77(1H, s), 5.72 (1H, s), 3.92 (2H, s), 1.17 (6H, s).

EXAMPLE NO. 77-Ethyl-3,3-dimethyl-5-(2-pyridyl)-2,3,4,5-tetrahydro-1-benzoxepine##STR112##

A solution of7-ethyl-3,3-dimethyl-5-(2-pyridyl)-2,3-dihydro-1-benzoxepine (75 g, 0.26mol) in 96% ethanol (95 ml) is placed in a 125 ml autoclave. Palladiumcontaining 50% moisture is then added (0.3 g at 10% on charcoal).

The hydrogen is introduced under pressure: 180 bar.

The whole mixture is stirred for 4 hours at 80° C.

The suspension is filtered and concentrated under reduced pressure.

[yellow oil; 78%]

IR in cm⁻¹ : 2960, 1590, 1570, 1495

¹ H NMR (CDCl₃) in ppm: 8.63 (1H, m), 7.30 (5H, m), 6.19 (1H, s), 4.54(1H, dd, J=2 Hz, J=9 Hz), 3.89 (1H, d, J=12 Hz), 3.48 (1H, d, J=12 Hz),2.42 (3H, m), 1.67 (1H, m), 1.20 (3H, s), 1.03 (3H, t), 0.85 (3H, s).

EXAMPLE NO. 83,3-Dimethyl-7-nitro-5-(4-nitro-2-pyridyl)-2,3-dihydro-1-benzoxepine##STR113##

A mixture of 3,3-dimethyl-5-(2-pyridyl)-1-benzoxepin-5-ol (5 g, 0.018mol) and of a commercial concentrated sulfuric acid solution (32 ml) iscooled to 0° C. Sodium nitrate (1.8 g, 0.02 mol) is added in portionsover 2 hours at 0° C. with stirring. The reaction mixture is then pouredinto ice-cold water (100 ml) and extracted with dichloromethane.

The organic phase is washed with water, dried over anhydrous sodiumsulfate and concentrated under reduced pressure.

[1.4 g; M.p.=180° C.; ethyl acetate; 25%]

IR in cm⁻¹ : 3100, 2970, 1545, 1530, 1480

¹ H NMR (CDCl₃) in ppm: 8.56 (1H, m), 8.34 (1H, d, J=2.50 Hz), 7.90 (1H,d, J=2.50 Hz), 7.48 (3H, m), 6.15 (1H, s), 4.15 (2H, s), 1.25 (6H, s).

By using the process described for Example 4, the following compoundsare prepared.

7-Bromo-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine##STR114##

[chromatography with silica gel and ethyl acetate; M.p.=158°-160° C.;ethyl acetate; 29%]

IR in cm⁻¹ : 3040, 2960, 1480

¹ H NMR (CDCl₃) in ppm: 8.25 (1H, m), 6.98 (6H, m), 5.82 (1H, s), 3.95(2H, s), 1.19 (6H, s).

    ______________________________________                                                   Elemental analysis                                                          C      H      Br       N    O                                        ______________________________________                                        % Found    59.24    4.68   23.09  3.91                                        % Calculated                                                                             58.97    4.66   23.08  4.05 9.24                                   ______________________________________                                    

7-Chloro-3,3-dimethyl-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine##STR115##

[M.p.=168°-170° C.; acetone; 15%]

IR in cm⁻¹ : 2960, 1480

¹ H NMR (CDCl₃) in ppm:8.25 (1H, m), 6.93 (6H, m), 5.84 (1H, s), 3.95(2H, s), 1.19 (6H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      Cl       N    O                                        ______________________________________                                        % Found    67.85    5.19   11.91  4.51                                        % Calculated                                                                             67.66    5.34   11.75  4.64 10.60                                  ______________________________________                                    

7-Fluoro-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine##STR116##

[M.p.=184°-185° C.; ethyl acetate; 28%]

IR in cm⁻¹ : 3050, 2950, 1490

¹ H NMR (CDCl₃) in ppm: 8.23 (1H, m), 6.75 (6H, m), 5.83 (1H, s), 3.96(2H, s), 1.19 (6H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      F        N    O                                        ______________________________________                                        % Found    71.62    5.57   6.91   4.81                                        % Calculated                                                                             71.56    5.65   6.66   4.91 11.22                                  ______________________________________                                    

3,3-Dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine ##STR117##

[M.p.=188°-189° C.; isopropanol; 19%]

IR in cm⁻¹ : 3050, 3010, 2960, 2870, 1605, 1570, 1490

¹ H NMR (CDCl₃) in ppm: 8.20 (1H, m), 6.91 (7H, m), 5.80 (1H, s), 4.00(2H, s), 1.21 (6H, s).

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      76.53  6.45       5.05                                           % Calculated 76.38  6.41       5.24 11.97                                     ______________________________________                                    

3,3,7-Trimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine##STR118##

[M.p.=146°-147° C.; ethyl acetate]

IR in cm⁻¹ : 3030, 2960, 2930, 2870, 1605, 1570, 1490

¹ H NMR (CDCl₃) in ppm: 8.23 (1H, m), 7.21 (3H, m), 6.89 (2H, m), 6.34(1H, m), 5.75 (1H, s), 3.95 (2H, s), 2.11 (3H, s), 2.11 (3H, s), 1.16(6H, s)

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      77.04  6.75       5.07                                           % Calculated 76.84  6.81       4.98 11.37                                     ______________________________________                                    

7-Ethyl-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine##STR119##

[M.p.=126°-129° C.; ethyl acetate/diisopropyl ether: 2/1; 20%]

IR in cm⁻¹ : 3030, 2960, 2930, 2870, 1610, 1575, 1500

¹ H NMR (CDCl₃) in ppm: 8.28 (1H, m), 7.23 (3H, m), 6.94 (2H, m), 6.38(1H, m), 5.78 (1H, s), 3.96 (2H, s), 2.43 (2H, q), 1.18 (6H, s), 1.04(3H, t).

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      77.48  7.26       4.79                                           % Calculated 77.26  7.17       4.74 10.83                                     ______________________________________                                    

7-Isopropyl-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine##STR120##

[M.p.=162°-164° C.; ethyl acetate]

IR in cm⁻¹ : 3025, 2950, 1500

¹ H NMR (CDCl₃) in ppm: 8.26 (1H, m), 7.08 (5H, m), 6.38 (1H, s), 5.75(1H, s), 3.95 (2H, s), 2.65 (1H, m), 1.10 (12H, m)

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      77.43  7.50       4.49                                           % Calculated 77.64  7.49       4.53 10.34                                     ______________________________________                                    

3,3-Dimethyl-7-(1-methylpropyl)-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine ##STR121##

[chromatography with silica gel and dichloromethane/methanol: 99/1;M.p.=110°-112° C.; cyclohexane]

IR in cm⁻¹ : 3030, 2950, 1605, 1500, 1480

¹ H NMR (CDCl₃) in ppm: 8.28 (1H, m), 7.20 (3H, m), 6.91 (2H, m), 6.33(1H, s), 5.77 (1H, s), 3.98 (2H, s), 2.32 (1H, m), 1.18 (6H, s), 1.05(8H, m)

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      77.93  7.81       4.24                                           % Calculated 77.98  7.79       4.33 9.89                                      ______________________________________                                    

7-Methoxy-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine##STR122##

[M.p.=164°-166° C.; ethyl acetate]

IR in cm⁻¹ : 3050, 2960, 1615, 1580, 1510, 1495

¹ H NMR (CDCl₃) in ppm: 8.20 (1H, m), 6.93 (5H, m), 6.14 (1H, m), 5.79(1H, s), 3.93 (2H, s), 3.56 (3H, s), 1.15 (6H, s)

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      73.00  6.49       4.71                                           % Calculated 72.70  6.44       4.71 16.14                                     ______________________________________                                    

3,3-Dimethyl-5-(2-pyridylN-oxide)-7-trifluoromethoxy-2,3-dihydro-1-benzoxepine ##STR123##

[M.p.=157°-159° C.; ethyl acetate]

IR in cm⁻¹ : 3070, 2970, 1495

¹ H NMR (CDCl₃) in ppm: 8.24 (1H, m), 7.14 (5H, m), 6.39 (1H, s), 5.85(1H, s), 3.96 (2H, s), 1.19 (6H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      F        N    O                                        ______________________________________                                        % Found    61.79    4.77   16.38  3.91                                        % Calculated                                                                             61.53    4.59   16.22  3.99 13.66                                  ______________________________________                                    

3,3-Dimethyl-5-(2-pyridylN-oxide)-7-trifluoromethyl-2,3-dihydro-1-benzoxepine ##STR124##

[M.p.=152°-153° C.; ethyl acetate/hexane: 1/2]

IR in cm⁻¹ : 3060, 2970, 1610, 1495

¹ H NMR (CDCl₃) in ppm: 8.20 (1H, m), 7.13 (6H, m), 5.89 (1H, s), 4.00(2H, s), 1.18 (6H, s)

    ______________________________________                                        Elemental analysis                                                                     C      H      F        N    O                                        ______________________________________                                        % Found    64.55    4.76   17.55  4.10                                        % Calculated                                                                             64.47    4.81   17.00  4.18 9.54                                   ______________________________________                                    

3,3-Dimethyl-7-methylsulfonyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine ##STR125##

[chromatography with silica gel and acetone; M.p.=200° C., diisopropylether]

IR in cm⁻¹ : 2970, 1600, 1565, 1490

¹ H NMR (CDCl₃) in ppm: 8.23 (1H, m), 7.65 (1H, m), 7.19 (5H, m), 5.97(1H, s), 4.04 (2H, s), 2.91 (3H, s), 1.22 (6H, s)

    ______________________________________                                        Elemental analysis                                                                     C      H      N        O    S                                        ______________________________________                                        % Found    62.86    5.64   3.95   18.25                                                                              9.25                                   % Calculated                                                                             62.59    5.54   4.06   18.53                                                                              9.28                                   ______________________________________                                    

3,3-Dimethyl-7-phenyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine##STR126##

[chromatography with silica gel and ethyl acetate/chloroform/methanolmixture: 60/30/10; M.p.=165°-168° C.; 35%]

IR in cm⁻¹ : 3050, 2960, 1605

¹ H NMR (CDCl₃) in ppm: 8.24 (1H, m), 7.08 (11H, m), 5.82 (1H, s), 3.98(2H, s), 1.16 (6H, s)

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      80.04  6.20       4.01                                           % Calculated 80.44  6.16       4.08 9.32                                      ______________________________________                                    

8-Bromo-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine##STR127##

[chromatography on silica gel and dichloromethane/methanol: 98/2;M.p.=135°-137° C.; diisopropyl ether/ethyl acetate: 60/40]

IR in cm⁻¹ : 3080, 2970, 1590, 1550, 1480

¹ H NMR (CDCl₃) in ppm: 8.21 (1H, m), 7.09 (5H, m), 6.40 (1H, d, J=8Hz), 5.81 (1H, s), 3.95 (2H, s), 1.17 (6H, s)

    ______________________________________                                        Elemental analysis                                                                     C      H      Br       N    O                                        ______________________________________                                        % Found    59.23    4.70   22.94  3.97                                        % Calculated                                                                             58.97    4.66   23.08  4.05 9.24                                   ______________________________________                                    

7-Cyano-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine##STR128##

[M.p.=206°-207° C.; ethyl acetate; 33%]

IR in cm⁻¹ : 2985, 2220, 1595, 1560, 1490

¹ H NMR (CF₃ COOD) in ppm: 8.79 (1H, m), 8.05 (4H, m), 7.25 (1H, d, J=8Hz), 6.88 (1H, d, J=2 Hz), 6.22 (1H, s), 4.15 (2H, s), 1.30 (6H, s)

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      74.09  5.57       9.40                                           % Calculated 73.95  5.52       9.58 10.95                                     ______________________________________                                    

8-Cyano-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine##STR129##

[chromatography with silica gel and dichloromethane/methanol: 98/2;M.p.=195°-7° C.; ethanol]

IR in cm⁻¹ : 3090, 2970, 2230, 1550

¹ H NMR (CDCl₃) in ppm: 8.20 (1H, m), 7.18 (5H, m), 6.64 (1H, d, J=8Hz), 5.95 (1H, s), 3.96 (2H, s), 1.20 (6H, s).

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      74.21  5.61       9.77                                           % Calculated 73.95  5.52       9.58 10.95                                     ______________________________________                                    

3,3-Dimethyl-5-(2-pyridylN-oxide)-8-trifluoromethyl-2,3-dihydro-1-benzoxepine ##STR130##

[M.p.=130°-131° C.; hexane; 25%]

IR in cm⁻¹ : 3060, 2960, 1570, 1485

¹ H NMR (CDCl₃) in ppm: 8.25 (1H, m), 7.03 (6H, s), 5.95 (1H, s), 4.01(2H, s), 1.19 (6H, s)

    ______________________________________                                        Elemental analysis                                                                     C      H      F        N    O                                        ______________________________________                                        % Found    64.74    4.93   17.00  4.18                                        % Calculated                                                                             64.47    4.81   17.00  4.18 9.54                                   ______________________________________                                    

3,3-Dimethyl-5-(2-pyridylN-oxide)-7-pentafluoroethyl-2,3-dihydro-1-benzoxepine ##STR131##

[M.p.=161°-162° C.; ethyl acetate]

IR in cm⁻¹ : 3070, 2970, 1610, 1585, 1600, 1590

¹ H NMR (CDCl₃) in ppm: 8.25 (1H, m), 7.98 (6H, m), 5.93 (1H, s), 4.03(2H, s), 1.20 (6H, s)

    ______________________________________                                        Elemental analysis                                                                     C      H      F        N    O                                        ______________________________________                                        % Found    59.52    4.31   24.27  3.62                                        % Calculated                                                                             59.22    4.19   24.65  3.64 8.30                                   ______________________________________                                    

3,3-Dimethyl-7-nitro-5-(4-nitro-2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine ##STR132##

[chromatography with silica gel and ethyl acetate/chloroform/methanol:60/30/10; M.p.=228° C.; methanol]

IR in cm⁻¹ : 3100, 2970, 1545, 1530, 1480

¹ H NMR (CDCl₃) in ppm: 8.37 (1H, d, J=2.70 Hz), 8.25 (1H, m, J=2.50Hz), 7.65 (1H, d, J=2.70 Hz), 7.38 (3H, m, J=2.50 Hz), 6.17 (1H, s),4.21 (2H, s), 1.28 (6H, s)

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      57.35  4.25       11.49                                          % Calculated 57.14  4.23       11.76                                                                              26.86                                     ______________________________________                                    

8-Cyano-3,3-dimethyl-1-(2-pyridylN-oxide)-4,5-dihydro-3H-benzo[f]cycloheptene ##STR133##

[chromatography with silica gel and cyclohexane/chloroform/methanolmixture: 70/20/10; M.p.=189° C., toluene; 42%]

IR in cm⁻¹ : 2950, 2225, 1595

¹ H NMR (CDCl₃) in ppm: 8.08 (1H, m), 7.27 (5H, m), 6.85 (1H, s), 5.92(1H, s), 2.93 (2H, m), 1.88 (2H, m), 0.95 (6H, m)

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      78.30  5.90       9.39                                           % Calculated 78.59  6.25       9.65 5.51                                      ______________________________________                                    

6,8-Dichloro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine ##STR134##

[M.p.=163°-164° C.; ethyl acetate]

IR in cm⁻¹ : 3050, 2970, 1590, 1550

¹ H NMR (CDCl₃) in ppm: 8.09 (1H, m), 7.47 (5H, m), 6.21 (1H, s), 4.00(2H, s), 1.15 (6H, s)

    ______________________________________                                        Elemental analysis                                                                     C      H      Cl       N    O                                        ______________________________________                                        % Found    60.75    4.70   21.26  4.12                                        % Calculated                                                                             60.73    4.50   21.09  4.17 9.52                                   ______________________________________                                    

7,8-Dichloro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine ##STR135##

[M.p.=173°-174° C.; ethyl acetate; 37%]

IR in cm⁻¹ : 3070, 2960, 1475

¹ H NMR (CDCl₃) in ppm: 8.20 (1H, m), 7.20 (4H, m), 6.60 (1H, s), 5.85(1H, s), 3.95 (2H, s), 1.15 (6H, s)

    ______________________________________                                        Elemental analysis                                                                     C      H      Cl       N    O                                        ______________________________________                                        % Found    60.47    4.46   21.11  4.12                                        % Calculated                                                                             60.73    4.50   21.09  4.17 9.52                                   ______________________________________                                    

7,9-Dichloro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine ##STR136##

[M.p.=155°-157° C.; diisopropyl ether/ethyl acetate: 70/30; 30%]

IR in cm⁻¹ : 3035, 1470, 1419

¹ H NMR (CDCl₃) in ppm: 8.22 (1H, m), 7.34 (4H, m), 6.42 (1H, d, J=2Hz), 5.88 (ZH, s), 4.02 (2H, s), 1.21 (6H, s)

    ______________________________________                                        Elemental analysis                                                                     C      H      Cl       N    O                                        ______________________________________                                        % Found    60.83    4.55   20.82  4.16                                        % Calculated                                                                             60.73    4.50   21.09  4.17 9.52                                   ______________________________________                                    

8,9-Dichloro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine ##STR137##

[M.p.=168° C.; ethyl acetate; 26%]

IR in cm⁻¹ : 2960, 1470, 1422

¹ H NMR (CDCl₃) in ppm: 8.20 (1H, m), 7.25 (3H, m), 6.95 (1H, d, J=8Hz), 6.42 (1H, d, J=8 Hz), 5.85 (1H, s), 4.07 (2H, s), 1.24 (6H, s)

    ______________________________________                                        Elemental analysis                                                                     C      H      Cl       N    O                                        ______________________________________                                        % Found    61.14    4.71   21.21  4.07                                        % Calculated                                                                             60.73    4.50   21.09  4.17 9.52                                   ______________________________________                                    

7,8-Difluoro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine ##STR138##

[M.p.=163°-165° C.; ethyl acetate]

IR in cm⁻¹ : 3060, 2965, 1600, 1515

¹ H NMR (CDCl₃) in ppm: 8.23 (1H, m), 7.28 (3H, m), 6.80 (1H, dd, J=7.0Hz), 6.35 (1H, dd, J=8.0 Hz), 5.80 (1H, s), 3.95 (2H, s), 1.18 (6H, s)

    ______________________________________                                        Elemental analysis                                                                     C      H      F        N    O                                        ______________________________________                                        % Found    67.36    4.56   12.73  4.95                                        % Calculated                                                                             67.32    4.99   12.53  4.62 10.55                                  ______________________________________                                    

8-Chloro-7-fluoro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine ##STR139##

[M.p.=149°-151° C.; ethyl acetate]

IR in cm⁻¹ : 3050, 2970, 1485

¹ H NMR (CDCl₃) in ppm: 8.20 (1H, m), 7.15 (4H, m), 6.35 (1H, d), 5.85(1H, s), 3.93 (2H, s), 1.14 (6H, s)

    ______________________________________                                        Elemental analysis                                                                     C    H       Cl     F     N    O                                     ______________________________________                                        % Found    64.04  4.82    11.16                                                                              5.91  4.41                                     % Calculated                                                                             63.85  4.73    11.09                                                                              5.94  4.38 10.01                               ______________________________________                                    

9-Ethyl-7-fluoro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine ##STR140##

[chromatography with silica gel and acetone/ethyl acetate mixture:50/50; M.p.=120°-2° C.; diisopropyl ether]

IR in cm⁻¹ : 2960, 2940, 1610, 1590

¹ H NMR (CDCl₃) in ppm: 8.20 (1H, m), 7.20 (3H, m), 6.69 (1H, dd, J=2Hz, J=8 Hz), 6.25 (1H, dd, J=2 Hz, J=10 Hz), 5.79 (1H, s), 3.94 (2H, s),2.66 (2H, q), 1.19 (6H, s), 1.16 (3H, t).

    ______________________________________                                        Elemental analysis                                                                     C      H      F        N    O                                        ______________________________________                                        % Found    73.12    6.54   6.18   4.58                                        % Calculated                                                                             72.82    6.43   6.06   4.47 10.21                                  ______________________________________                                    

7,8-Dimethoxy-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine ##STR141##

[chromatography with silica gel and dichloromethane/methanol: 98/2; M.p.146° C.; ethyl acetate]

IR in cm⁻¹ : 3110, 2950, 1615, 1520, 1490

¹ H NMR (CDCl₃) in ppm: 8.26 (1H, m), 7.25 (3H, m), 6.57 (1H, s), 6.08(1H, s), 5.70 (1H, s), 3.99 (2H, s), 3.81 (3H, s), 3.56 (3H, s), 1.19(6H, s).

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      69.86  6.70       4.12                                           % Calculated 69.70  6.47       4.28 19.55                                     ______________________________________                                    

7-Cyano-3,3,8-trimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine##STR142##

[chromatography with silica gel and chloroform/methanol mixture: 98/2;M.p.=230°-235° C.; toluene/diisopropyl ether]

IR in cm⁻¹ : 3060, 2950, 2210, 1605, 1495

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      74.39  6.00       8.93                                           % Calculated 74.49  5.92       9.15 10.45                                     ______________________________________                                    

8-Cyano-3,3,7-trimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine##STR143##

[M.p.=182° C.; toluene; 30%]

IR in cm⁻¹ : 3070, 2960, 2225, 1605, 1545, 1490

¹ H NMR (CDCl₃) in ppm: 8.20 (1H, m), 7.22 (4H, m), 6.44 (1H, s), 5.90(1H, s), 3.92 (2H, s), 2.26 (3H, s), 1.18 (6H, s)

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      74.70  5.91       9.04                                           % Calculated 74.49  5.92       9.15 10.45                                     ______________________________________                                    

3,3-Dimethyl-5-(2-pyridyl N-oxide)-2,3,7,8,9,10-hexahydro-1-naphth[2,3-b]oxepine ##STR144##

[chromatography with silica gel and dichloromethane/methanol: 98/2;M.p.=184° C.; toluene]

IR in cm⁻¹ : 2930, 1610, 1550, 1500

¹ H NMR (CDCl₃) in ppm: 8.22 (1H, m), 7.22 (3H, m), 6.72 (1H, s), 6.24(1H, s), 5.69 (1H, s), 3.95 (2H, s), 2.58 (4H, m), 1.70 (4H, m), 1.16(6H, s).

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      78.30  7.39       4.48                                           % Calculated 78.47  7.21       4.36 9.96                                      ______________________________________                                    

7-Ethyl-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3,4,5-tetrahydro-1-benzoxepine ##STR145##

[m.p.=88°-89° C.; diisopropyl ether]

IR in cm⁻¹ : 3060, 3020, 2960, 2930, 2870, 1610, 1490

¹ H NMR (CDCl₃) in ppm: 8.28 (1H, m), 7.16 (3H, m), 6.96 (2H, m), 6.45(1H, m), 5.20 (1H, dd, J=2 Hz, J=9 Hz), 3.71 (2H, s), 2.50 (3H, m), 1.70(1H, dd, J=2 Hz, J=13.5 Hz), 1.07 (3H, s), 1.06 (3H, t), 0.80 (3H, s)

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      76.63  7.75       4.62                                           % Calculated 76.73  7.80       4.71 10.76                                     ______________________________________                                    

7-Bromo-3,3-dimethyl-5-(3-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine##STR146##

[M.p.=161°-162° C.; ethyl acetate; 50%]

IR in cm⁻¹ : 3090, 2950, 1580, 1540, 1460

¹ H NMR (CDCl₃) in ppm: 8.19 (2H, m), 7.23 (3H, m), 6.90 (2H, m), 5.77(1H, s), 3.90 (2H, s), 1.17 (6H, s)

    ______________________________________                                        Elemental analysis                                                                     C      H      Br       N    O                                        ______________________________________                                        % Found    59.07    4.72   22.99  4.13                                        % Calculated                                                                             58.97    4.66   23.06  4.05 9.26                                   ______________________________________                                    

7-Cyano-3,3-dimethyl-5-(3-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine##STR147##

[M.p.=162°-164° C.; ethyl acetate; 45%]

IR in cm⁻¹ : 3070, 2960, 2230, 1600

¹ H NMR (CDCl₃) in ppm: 8.17 (2H, m), 7.25 (5H, m), 5.85 (1H, s), 3.92(2H, s), 1.15 (6H, s)

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      73.89  5.52       9.68                                           % Calculated 73.95  5.52       9.58 10.95                                     ______________________________________                                    

7,8-Dichloro-3,3-dimethyl-5-(3-pyridylN-oxide)-2,3-dihydro-1-benzoxepine ##STR148##

[137°-139° C.; isooctane and diisopropyl ether: 50/50; 46%]

IR in cm⁻¹ : 3120, 3030, 2950, 1590, 1540

¹ H NMR (CDCl₃) in ppm: 8.20 (2H, m), 7.16 (3H, m), 6.80 (1H, s), 5.79(1H, s), 3.90 (2H, s), 1.19 (6H, s)

    ______________________________________                                        Elemental analysis                                                                     C      H      Cl       N    O                                        ______________________________________                                        % Found    60.70    4.54   21.24  4.05                                        % Calculated                                                                             60.73    4.50   21.09  4.17 9.52                                   ______________________________________                                    

3,3-Dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine-7-carboxamide ##STR149##

[M.p.=215°-217° C.; methanol; 28%]

IR in cm⁻¹ : 3400, 3200, 2970, 1665, 1605

¹ H NMR (DMSO) in ppm: 8.16 (1H, m), 7.35 (6H, m), 5.85 (1H, s), 3.93(2H, s), 1.13 (6H, s).

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      69.49  5.84       8.80                                           % Calculated 69.66  5.85       9.03 15.47                                     ______________________________________                                    

3,3-Dimethyl-7-phenylsulfonyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine ##STR150##

[M.p.=167°-169° C.; diisopropyl ether; 19%]

IR in cm⁻¹ : 3060, 2950, 1600, 1560, 1490

¹ H NMR (CDCl₃) in ppm: 8.20 (1H, m), 7.38 (11H, m), 5.93 (1H, s), 3.99(2H, s), 1.19 (6H, s)

    ______________________________________                                        Elemental analysis                                                                     C      H      N        O    S                                        ______________________________________                                        % Found    67.84    5.34   3.42   15.57                                                                              7.83                                   % Calculated                                                                             67.79    5.20   3.44   15.71                                                                              7.87                                   ______________________________________                                    

7-Chloro-8-ethyl-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine ##STR151##

[M.p.=144°-146° C.; ethyl acetate; 34%]

IR in cm⁻¹ : 3070, 2950, 1485

¹ H NMR (CDCl₃) in ppm: 8.23 (1H, m), 7.20 (3H, m), 6.87 (1H, s), 6.50(1H, s), 5.78 (1H, s), 3.95 (2H, s), 2.62 (2H, q), 1.18 (3H, t), 1.15(6H, s)

    ______________________________________                                        Elemental analysis                                                                     C      H      Cl       N    O                                        ______________________________________                                        % Found    69.25    6.01   10.89  4.26                                        % Calculated                                                                             69.19    6.11   10.75  4.25 9.70                                   ______________________________________                                    

8-Bromo-3,3-dimethyl-1-(2-pyridyl N-oxide)-3H-benzo[f]-cyclohepta-1,4-diene ##STR152##

[M.p.=167° C.; diisopropyl ether; 10%]

IR in cm⁻¹ : 3080, 2980, 1485

¹ H NMR (CDCl₃) in ppm: 8.11 (1H, m), 7.15 (6H, m), 6.52 (1H, d, J=10Hz), 5.88 (1H, s), 5.75 (1H, d, J=10 Hz), 1.11 (6H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      Br       N    O                                        ______________________________________                                        % Found    63.16    4.56   23.05  4.09                                        % Calculated                                                                             63.17    4.71   23.35  4.09 4.68                                   ______________________________________                                    

3,3-Dimethyl-7-(2-methylpropyl)-5-(2-pyridyl-N-oxide)-2,3-dihydro-1-benzoxepine##STR153##

[M.p.=114°-116° C.; diisopropyl ether; 25%]

IR in cm⁻¹ : 3060; 2960; 1500; 1490

¹ H NMR (CDCl₃) in ppm:8,20(1H, m); 7,20(3H, m); 6,86(2H, m); 6,30(1H,s); 5,76(1H, s); 3,95(2H, s); 2,22(2H, d); 1,68(1H, m); 1,16(6H, s);0,8(3H, s); 0,58(3H, s).

    ______________________________________                                        Elemental analysis                                                                       C    H          N      O                                           ______________________________________                                        % Found      77,92  7,55       4,42                                           % Calculated 77,98  7,79       4,33 9,89                                      ______________________________________                                    

7-Chloro-3,3,8-trimethyl-5-(2-pyridyl-N-oxide)-2,3-dihydro-1-benzoxepine##STR154##

[M.p.=178°-180° C.; ethyl acetate; 20%]

IR in cm⁻¹ : 3060; 2960; 1610; 1490

¹ H NMR (CDCl₃) in ppm: 8,19(1H, m); 7,20(3H, m); 6,85(1H, s); 6,49(1H,s); 5,75(1H, s); 3,92(2H, s); 2,22(3H, s); 1,15(6H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      Cl       N    O                                        ______________________________________                                        % Found    68,74    5,73   11,38  4,42                                        % Calculated                                                                             68,48    5,75   11,23  4,44 10,13                                  ______________________________________                                    

7-Bromo-8-chloro-3,3-dimethyl-5-(2-pyridyl-N-oxyde)-2,3-dihydro-1-benzoxepine##STR155##

[M.p.=182°-183° C.; ethyl acetate; 44%]

IR in cm⁻¹ : 3060; 2950; 1580; 1540; 1470

¹ H NMR (CDCl₃) in ppm: 8,22(1H, m); 7,22(3H, m); 7,08(1 H, s); 6,72(1H,s); 5,83(1H, s); 3,95(2H, s); 1,17(6H, s).

    ______________________________________                                        Elemental analysis                                                                     C    H       Br     Cl    N    O                                     ______________________________________                                        % Found    53,72  3,87    20,89                                                                              9,46  3,75                                     % Calculated                                                                             53,63  3,97    20,99                                                                              9,31  3,68 8,41                                ______________________________________                                    

8-Chloro-7-cyano-3,3-dimethyl-5-(2-pyridyl-N-oxide)-2,3-dihydro-1-benzoxepine##STR156##

[M.p.=206°-207° C.; ethyl acetate; 53%]

IR in cm⁻¹ : 3080; 2990; 2240; 1600; 1550; 1490

¹ H NMR (CDCl₃) in ppm: 8,20(1H, m); 7,23(3H, m); 7,13(1H, s); 6,83(1H,s); 5,93(1H, s); 4,02(2H, s); 1,20(6H, s),

    ______________________________________                                        Elemental analysis                                                                     C      H      Cl       N    O                                        ______________________________________                                        % Found    65,51    4,56   10,89  8,48                                        % Calculated                                                                             66,16    4,63   10,85  8,57 9,79                                   ______________________________________                                    

8-Chloro-3,3-dimethyl-5-(2-pyridyl-N-oxide)-7-trifluoromethyl-2,3-dihydro-1-benzoxepine##STR157##

[M.p.=158°-161° C.]

IR in cm⁻¹ : 3080; 2980; 1610; 1565; 1495

¹ H NMR (CDCl₃) in ppm: 8,18(1H, m); 7.58(4H, m); 6,80(1H, s); 5,88(1H,s); 3,98(2H, s); 1,15(6H, s).

    ______________________________________                                        Elemental analysis                                                                     C    H       Cl     F     N    O                                     ______________________________________                                        % Found    58,42  4,24    9,99 14,79 3,83                                     % Calculated                                                                             58,46  4,09    9,59 15,42 3,79 8,65                                ______________________________________                                    

8-Bromo-3,3-dimethyl-1-(2-pyridyl-N-oxide)-4,5-dihydro-3H-benzo[f]-cyclohept-1-ene ##STR158##

[M.p.=173°-175° C.; toluene; 43%]

IR in cm⁻¹ : 3070; 2960; 1590; 1490

1H NMR (CDCl₃) in ppm: 8,11(1H, m); 7,18(5H, m); 6,73(1H, d); 5,90(1H,s); 2,59(2H, m); 1,85(2H, m); 1,09(6H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      Br       N    O                                        ______________________________________                                        % Found    62,80    5,25   23,26  3,93                                        % Calculated                                                                             62,80    5,27   23,21  4,07 4,65                                   ______________________________________                                    

3,3-Dimethyl-8-phenylsulfonyl-1-(2-pyridyl-N-oxide)-4,5-dihydro-3H-benzo[f]cyclohept-1-ene##STR159##

[M.p.=191°-192° C.; isopropanol; 45%]

IR in cm⁻¹ : 3060; 2950; 1595; 1585; 1560; 1485

¹ NMR (CDCl₃) in ppm: 8,08(1H, m); 7,45(11H, m); 5,95(1H, s); 2,92(2H,m); 1,88(2H), m); 1,10(6H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      N        O    S                                        ______________________________________                                        % Found    70,86    5,82   3,34        7,83                                   % Calculated                                                                             71,08    5,72   3,45   11,84                                                                              7,91                                   ______________________________________                                    

7,8-Dichloro-3,3-dimethyl-1-(2-pyridyl-N-oxide)-4,5-dihydro-3H-benzo[f]cyclohept-1-ene##STR160##

[M.p.=195°-196° C.; toluene; 25%]

IR in cm⁻¹ : 3070; 2970; 1550; 1480

¹ H NMR (CDCl₃) in ppm: 8,12(1H, m); ? ,25(41H, m); 6,68(1H, s);5,92(1H, s); 2,61(2H, m); 1,85(2H, m); 1,11(6H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      Cl       N    O                                        ______________________________________                                        % Found    64,32    5,17   21,10  4,31                                        % Calculated                                                                             64,38    5,13   21,22  4,19 4,79                                   ______________________________________                                    

8-Bromo-4,4-dimethyl-1-(2-pyridyl-N-oxide)-3,4-dihydro-3H-benzo[f]cyclohept-1-ene##STR161##

[M.p.=137°-139° C.; diisopropyl ether; 20%]

IR in cm⁻¹ : 2960; 2930; 1610; 1590; 1550; 1490 ¹ H NMR (CDCl₃) in ppm:8,12(1H, m); 7,12(6H, m); 6,51 (1H, d); 2,58(2H, s); 1,74(2H, d);1,05(6H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      Br       N    O                                        ______________________________________                                        % Found    62,80    5,14   23,27  4,04                                        % Calculated                                                                             62,80    5,27   23,21  4,07 4,65                                   ______________________________________                                    

Hemisulfate of7-fluoro-3,3-dimethyl-5(2-pyridyl-N-oxide)-2,3-dihydro-1-benzoxepine##STR162##

[M.p.=198°-199° C.; ethanol; 33%]

IR in cm⁻¹ : 3090; 2970; 1620; 1580; 1500

¹ H NMR (CDCl₃) in ppm: 10,28(1H, s); 8,36(1H, m); 7,55(3H, m); 6,99(2H,m); 6,07(2H, m); 3,90(2H, s); 1,14(6H, s).

    ______________________________________                                        Elemental analysis                                                                     C    H       F      N     O    S                                     ______________________________________                                        % Found    61,06  5,45    5,46 4,19       5,01                                % Calculated                                                                             61,07  5,12    5,68 4,19  19,14                                                                              4,80                                ______________________________________                                    

Hydrochloride of7,8-dichloro-3,3-dimethyl-5-(2-pyridyl-N-oxide)-2,3-dihydro-1-benzoxepine##STR163##

[M.p.=182°-186° C.; acetone; 60%]

IR in cm⁻¹ : 3090; 2970; 2270; 1700; 1605; 1525

¹ H NMR (CDCl₃) in ppm: 11,78(1 H, s); 8,43(1H, m); 7,63(3H, m);7,26(1H, s); 6,55(1H, s); 6,00(1H, s); 3,95(2H, s); 1,15(6H, s).

    ______________________________________                                        Elemental analysis                                                                     C      H      Cl       N    O                                        ______________________________________                                        % Found    54,74    4,24   27,89  3,90                                        % Calculated                                                                             54,78    4,33   28,54  3,76 8,59                                   ______________________________________                                    

EXAMPLE 9 4-(4-Fluorophenoxy)-3.3-dimethyl-butanoic acid ##STR164##

A suspension of 4-fluorophenol(21.3 g; 0.19 mol) and sodium hydroxide(7.6 g; 0.19 mol) in n-butanol under a flow of dry nitrogene is heatedby an oil bath at 190° C. during 10 minutes. The reactor is equippedwith a distillation system for the elimination of the formed water byazeotropic removal. The heating is continued to distill all of then-butanol. Then the 3.3-dimethylbutyrolacetone (22.8 g; 0.20 mol) isadded. The reaction medium is heated 10 hours at 160° C. (temperatureinside the medium), then cooled to 80° C. for the addition of water (65ml). The obtained solution is washed with dichloromethane and decanted.The aqueous phase is acidified and the desired acid is extracted withdichloromethane dried over anhydrous sodium sulfate. The solution isconcentrated under reduced pressure and the oily residue is distilled.

[B.p.(53.2 Pa=0.4 mm Hg)=130°-134° C.; 75%]

IR in cm⁻¹ : 3480; 2200; 1705; 1600; 1505

¹ H NMR (CDCl₃) in ppm: 10.75 (1H, m); 6.82 (4H, m); 3.66 (2H, S); 2.40(2H, S); 1.11 (6H, S).

We claim:
 1. A compound of the formula: ##STR165## in which: Xrepresents O,R₁, R₂, R₃ and R₄, which are identical or different,represent a hydrogen atom or a C₁ -C₇ alkyl group; R₅ represents ahydrogen atom or a hydroxyl group; R₆ represents a 2-pyridyl, 2-pyridylN-oxide, 3-pyridyl, 3-pyridyl N-oxide, 4-pyridyl, 3-hydroxy-4-pyridylgroup, optionally substituted on the carbon atoms by 1 to 3 substituentschosen from hydroxyl, nitro, cyano, C₁ -C₇ alkyl and C₁ -C₇ alkoxy; R₇represents a hydrogen atom or a hydroxyl, C₁ -C₇ alkoxy or C₁ -C₇acyloxy group; R₈ and R₉, which are identical or different, represent ahydrogen or halogen atom, a hydroxyl, nitro, cyano, trifluoromethyl,trifluoromethoxy, pentafluoroethyl, C₁ -C₇ alkyl, C₁ -C₇ alkoxy, C₁ -C₇alkylthio, C₁ -C₇ acylthio, C₁ -C₇ alkylsulfonyl or C₁ -C₇ alkylsulfinylgroup, a group of formulae: ##STR166## in which R₁₂ and R₁₃ which areidentical or different, represent a hydrogen atom or a C₁ -C₇ alkylgroup, or R₈ and R₉ represent a C₆ -C₁₀ aryl, (C₆ -C₁₀)-arylsulfonyl or(C₆ -C₁₀)arylsulfinyl group, optionally substituted by one to sixsubstituents chosen from halo, hydroxyl, nitro, cyano, carboxyl,carbamoyl, trifluoromethyl, trifluoromethoxy, pentafluoroethyl, C₁ -C₇alkyl, C₁ -C₇ alkoxy, C₁ -C₇ alkylthio, C₁ -C₇ acylthio, C₁ -C₇alkylsulfonyl or C₁ -C₇ alkylsulfinyl, or R₈ and R₉ together form agroup (CH₂)_(n), n being 4, an N-oxide thereof or a pharmaceuticallyacceptable salt thereof.
 2. A compound of formula I according to claim1, wherein R₁ and R₂ represent a hydrogen atom.
 3. A compound of formulaI according to claim 1, wherein R₅ represents a hydrogen atom.
 4. Acompound of formula I according to claim 1, wherein R₆ is chosen from2-pyridyl, 2-pyridyl N-oxide, 3-pyridyl, 3-pyridyl N-oxide, 4-pyridyland 3-hydroxy-4-pyridyl.
 5. A compound of formula I according to claim1, wherein R₇ represents a hydrogen atom or a hydroxyl, methoxy oracetoxy group.
 6. A compound according to claim 1 of the formula:##STR167## in which R₅, R₆, R₇, R₈ and R₉ are as defined in claim
 1. 7.A compound according to claim 1 of the formula: ##STR168## in which R₆,R₈ and R₉ are as defined in claim
 1. 8. A compound according to claim 1,which is chosen from:3,3-dimethyl-5-(2-pyridylN-oxide)-7-trifluoromethoxy-2,3-dihydro-1-benzoxepine;3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;7-fluoro-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;7-bromo-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;8-bromo-3,3,7-trimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;7-ethyl-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;3,3-dimethyl-5-(2-pyridylN-oxide)-7-(1-methylpropyl)-2,3-dihydro-1-benzoxepine;7-isopropyl-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine; 7-methoxy-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine; 3,3-dimethyl-5-(2-pyridylN-oxide)-7-methylsulfinyl-2,3-dihydro-1-benzoxepine;3,3-dimethyl-5-(2-pyridylN-oxide)-7-methylsulfonyl-2,3-dihydro-1-benzoxepine;3,3-dimethyl-5-(2-pyridylN-oxide)-7-pentafluoroethyl-2,3-dihydro-1-benzoxepine;3,3-dimethyl-5-(2-pyridylN-oxide)-7-trifluoromethyl-2,3-dihydro-1-benzoxepine;8-bromo-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;7-bromo-3,3-dimethyl-5-(3-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine; 3.3-dimethyl-7-nitro-5-(4-nitro-2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine;3,3-dimethyl-7-phenyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine; 8-cyano-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine;6,8-dichloro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine;7,9-dichloro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine;8,9-dichloro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine;7,8-dimethoxy-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine;9-ethyl-7-fluoro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine;7-chloro-8-fluoro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine;7,8-dichloro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepin-5-ol;7-chloro-8-ethyl-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine.
 9. Compounds of claim 1, which ischosen from:7-chloro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine; 3,3-dimethyl-5-(2-pyridylN-oxide)-7-trifluoromethyl-2,3-dihydro-1-benzoxepine;7-cyano-3,3-dimethyl-5-(2-pyridyl N-oxide)-2,3-dihydro-1-benzoxepine;8-cyano-3,3-dimethyl-1-(2-pyridylN-oxide)-4,5-dihydro-3H-benzo[f]cycloheptene; 7.8-dichloro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine;7,8-difluoro-3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine; 7-cyano-3,3,8-trimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine; 8-cyano-3,3,7-trimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine; 3,3-dimethyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine-7-carboxamide; and3,3-dimethyl-7-phenylsulfonyl-5-(2-pyridylN-oxide)-2,3-dihydro-1-benzoxepine.
 10. Pharmaceutical compositioncomprising, as active ingredient, a compound according to claim 1 and apharmaceutically acceptable vehicle.